RBCC Red Blood Cell Collection

STAT3 (APRF) [Confidence: low (only semi-automatic identification from reviews)]
Signal transducer and activator of transcription 3 (Acute-phase response factor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P40763
ID STAT3_HUMAN Reviewed; 770 AA.
AC P40763; A8K7B8; O14916; Q9BW54;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
read moreDT 07-JUN-2004, sequence version 2.
DT 22-JAN-2014, entry version 154.
DE RecName: Full=Signal transducer and activator of transcription 3;
DE AltName: Full=Acute-phase response factor;
GN Name=STAT3; Synonyms=APRF;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT TYR-561.
RC TISSUE=Placenta;
RX PubMed=7512451; DOI=10.1016/0092-8674(94)90235-6;
RA Akira S., Nishio Y., Inoue M., Wang X.-J., Wei S., Matsusaka T.,
RA Yoshida K., Sudo T., Naruto M., Kishimoto T.;
RT "Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-
RT related transcription factor involved in the gp130-mediated signaling
RT pathway.";
RL Cell 77:63-71(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9630560; DOI=10.1016/S0378-1119(98)00185-1;
RA Della Pietra L., Bressan A., Pezzotti A., Serlupi-Crescenzi O.;
RT "Highly conserved amino-acid sequence between murine STAT3 and a
RT revised human STAT3 sequence.";
RL Gene 213:119-124(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ILE-143.
RG SeattleSNPs variation discovery resource;
RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND DEL-701).
RC TISSUE=Kidney, and Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 564-704.
RC TISSUE=Liver;
RA Della Pietra L., Bressan A., Pezzotti A.R., Serlupi-Crescenzi O.;
RL Submitted (OCT-1997) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP PHOSPHORYLATION AT SERINE RESIDUES.
RX PubMed=7701321; DOI=10.1126/science.7701321;
RA Zhang X., Blenis J., Li H.-C., Schindler C., Chen-Kiang S.;
RT "Requirement of serine phosphorylation for formation of STAT-promoter
RT complexes.";
RL Science 267:1990-1994(1995).
RN [8]
RP INTERACTION WITH PIAS3.
RX PubMed=9388184; DOI=10.1126/science.278.5344.1803;
RA Chung C.D., Liao J., Liu B., Rao X., Jay P., Berta P., Shuai K.;
RT "Specific inhibition of Stat3 signal transduction by PIAS3.";
RL Science 278:1803-1805(1997).
RN [9]
RP PHOSPHORYLATION BY BMX, INTERACTION WITH BMX, AND FUNCTION.
RX PubMed=10688651; DOI=10.1128/MCB.20.6.2043-2054.2000;
RA Tsai Y.T., Su Y.H., Fang S.S., Huang T.N., Qiu Y., Jou Y.S.,
RA Shih H.M., Kung H.J., Chen R.H.;
RT "Etk, a Btk family tyrosine kinase, mediates cellular transformation
RT by linking Src to STAT3 activation.";
RL Mol. Cell. Biol. 20:2043-2054(2000).
RN [10]
RP FUNCTION IN IL6 SIGNALING, PHOSPHORYLATION, AND DEPHOSPHORYLATION BY
RP PTPN2.
RX PubMed=12359225; DOI=10.1016/S0006-291X(02)02291-X;
RA Yamamoto T., Sekine Y., Kashima K., Kubota A., Sato N., Aoki N.,
RA Matsuda T.;
RT "The nuclear isoform of protein-tyrosine phosphatase TC-PTP regulates
RT interleukin-6-mediated signaling pathway through STAT3
RT dephosphorylation.";
RL Biochem. Biophys. Res. Commun. 297:811-817(2002).
RN [11]
RP INTERACTION WITH NCOA1.
RX PubMed=11773079; DOI=10.1074/jbc.M111486200;
RA Giraud S., Bienvenu F., Avril S., Gascan H., Heery D.M., Coqueret O.;
RT "Functional interaction of STAT3 transcription factor with the
RT coactivator NcoA/SRC1a.";
RL J. Biol. Chem. 277:8004-8011(2002).
RN [12]
RP INTERACTION WITH HCV CORE PROTEIN.
RX PubMed=12208879; DOI=10.1084/jem.20012127;
RA Yoshida T., Hanada T., Tokuhisa T., Kosai K., Sata M., Kohara M.,
RA Yoshimura A.;
RT "Activation of STAT3 by the hepatitis C virus core protein leads to
RT cellular transformation.";
RL J. Exp. Med. 196:641-653(2002).
RN [13]
RP INTERACTION WITH IL23R.
RX PubMed=12023369;
RA Parham C., Chirica M., Timans J., Vaisberg E., Travis M., Cheung J.,
RA Pflanz S., Zhang R., Singh K.P., Vega F., To W., Wagner J.,
RA O'Farrell A.-M., McClanahan T.K., Zurawski S., Hannum C., Gorman D.,
RA Rennick D.M., Kastelein R.A., de Waal Malefyt R., Moore K.W.;
RT "A receptor for the heterodimeric cytokine IL-23 is composed of IL-
RT 12Rbeta1 and a novel cytokine receptor subunit, IL-23R.";
RL J. Immunol. 168:5699-5708(2002).
RN [14]
RP FUNCTION IN EGFR SIGNALING, AND INTERACTION WITH EGFR.
RX PubMed=12873986;
RA Shao H., Cheng H.Y., Cook R.G., Tweardy D.J.;
RT "Identification and characterization of signal transducer and
RT activator of transcription 3 recruitment sites within the epidermal
RT growth factor receptor.";
RL Cancer Res. 63:3923-3930(2003).
RN [15]
RP PHOSPHORYLATION AT TYR-705 AND SER-727.
RX PubMed=12763138; DOI=10.1016/S0301-472X(03)00045-6;
RA Wierenga A.T., Vogelzang I., Eggen B.J., Vellenga E.;
RT "Erythropoietin-induced serine 727 phosphorylation of STAT3 in
RT erythroid cells is mediated by a MEK-, ERK-, and MSK1-dependent
RT pathway.";
RL Exp. Hematol. 31:398-405(2003).
RN [16]
RP REVIEW ON ROLE IN KIT SIGNALING.
RX PubMed=15526160; DOI=10.1007/s00018-004-4189-6;
RA Ronnstrand L.;
RT "Signal transduction via the stem cell factor receptor/c-Kit.";
RL Cell. Mol. Life Sci. 61:2535-2548(2004).
RN [17]
RP FUNCTION, AND INTERACTION WITH IL31RA.
RX PubMed=15194700; DOI=10.1074/jbc.M401122200;
RA Dreuw A., Radtke S., Pflanz S., Lippok B.E., Heinrich P.C.,
RA Hermanns H.M.;
RT "Characterization of the signaling capacities of the novel gp130-like
RT cytokine receptor.";
RL J. Biol. Chem. 279:36112-36120(2004).
RN [18]
RP PHOSPHORYLATION AT SER-727 BY IRAK1.
RX PubMed=15465816; DOI=10.1074/jbc.M410369200;
RA Huang Y., Li T., Sane D.C., Li L.;
RT "IRAK1 serves as a novel regulator essential for lipopolysaccharide-
RT induced interleukin-10 gene expression.";
RL J. Biol. Chem. 279:51697-51703(2004).
RN [19]
RP INTERACTION WITH TMF1.
RX PubMed=15467733; DOI=10.1038/sj.onc.1208149;
RA Perry E., Tsruya R., Levitsky P., Pomp O., Taller M., Weisberg S.,
RA Parris W., Kulkarni S., Malovani H., Pawson T., Shpungin S., Nir U.;
RT "TMF/ARA160 is a BC-box-containing protein that mediates the
RT degradation of Stat3.";
RL Oncogene 23:8908-8919(2004).
RN [20]
RP INTERACTION WITH PELP1.
RX PubMed=15994929; DOI=10.1158/0008-5472.CAN-04-4664;
RA Manavathi B., Nair S.S., Wang R.-A., Kumar R., Vadlamudi R.K.;
RT "Proline-, glutamic acid-, and leucine-rich protein-1 is essential in
RT growth factor regulation of signal transducers and activators of
RT transcription 3 activation.";
RL Cancer Res. 65:5571-5577(2005).
RN [21]
RP PHOSPHORYLATION AT SER-727 BY ZIPK/DAPK3, INTERACTION WITH ZIPK/DAPK3,
RP AND SUBCELLULAR LOCATION.
RX PubMed=16219639; DOI=10.1093/intimm/dxh331;
RA Sato N., Kawai T., Sugiyama K., Muromoto R., Imoto S., Sekine Y.,
RA Ishida M., Akira S., Matsuda T.;
RT "Physical and functional interactions between STAT3 and ZIP kinase.";
RL Int. Immunol. 17:1543-1552(2005).
RN [22]
RP INTERACTION WITH SOCS7.
RX PubMed=15677474; DOI=10.1074/jbc.M411596200;
RA Martens N., Uzan G., Wery M., Hooghe R., Hooghe-Peters E.L.,
RA Gertler A.;
RT "Suppressor of cytokine signaling 7 inhibits prolactin, growth
RT hormone, and leptin signaling by interacting with STAT5 or STAT3 and
RT attenuating their nuclear translocation.";
RL J. Biol. Chem. 280:13817-13823(2005).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-705, PHOSPHORYLATION
RP [LARGE SCALE ANALYSIS] AT TYR-704 (ISOFORM DEL-701), AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [24]
RP PHOSPHORYLATION AT TYR-705 BY PTK6.
RX PubMed=16568091; DOI=10.1038/sj.onc.1209501;
RA Liu L., Gao Y., Qiu H., Miller W.T., Poli V., Reich N.C.;
RT "Identification of STAT3 as a specific substrate of breast tumor
RT kinase.";
RL Oncogene 25:4904-4912(2006).
RN [25]
RP INTERACTION WITH PRKCE, AND PHOSPHORYLATION AT SER-727.
RX PubMed=17875724; DOI=10.1158/0008-5472.CAN-07-1604;
RA Aziz M.H., Manoharan H.T., Church D.R., Dreckschmidt N.E., Zhong W.,
RA Oberley T.D., Wilding G., Verma A.K.;
RT "Protein kinase Cepsilon interacts with signal transducers and
RT activators of transcription 3 (Stat3), phosphorylates Stat3Ser727, and
RT regulates its constitutive activation in prostate cancer.";
RL Cancer Res. 67:8828-8838(2007).
RN [26]
RP SUBCELLULAR LOCATION, AND NUCLEAR IMPORT MOTIF.
RX PubMed=15919823; DOI=10.1073/pnas.0501643102;
RA Liu L., McBride K.M., Reich N.C.;
RT "STAT3 nuclear import is independent of tyrosine phosphorylation and
RT mediated by importin-alpha3.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:8150-8155(2005).
RN [27]
RP INTERACTION WITH CDK9.
RX PubMed=17956865; DOI=10.1074/jbc.M706458200;
RA Hou T., Ray S., Brasier A.R.;
RT "The functional role of an interleukin 6-inducible CDK9.STAT3 complex
RT in human gamma-fibrinogen gene expression.";
RL J. Biol. Chem. 282:37091-37102(2007).
RN [28]
RP PHOSPHORYLATION AT SER-727 BY DYRK2.
RX PubMed=18599021; DOI=10.1016/j.bcp.2008.05.021;
RA Yoshida K.;
RT "Role for DYRK family kinases on regulation of apoptosis.";
RL Biochem. Pharmacol. 76:1389-1394(2008).
RN [29]
RP IDENTIFICATION IN A COMPLEX WITH LYN AND PAG1.
RX PubMed=18070987; DOI=10.1182/blood-2007-05-090985;
RA Tauzin S., Ding H., Khatib K., Ahmad I., Burdevet D.,
RA van Echten-Deckert G., Lindquist J.A., Schraven B., Din N.U.,
RA Borisch B., Hoessli D.C.;
RT "Oncogenic association of the Cbp/PAG adaptor protein with the Lyn
RT tyrosine kinase in human B-NHL rafts.";
RL Blood 111:2310-2320(2008).
RN [30]
RP INTERACTION WITH ARL2BP, PHOSPHORYLATION AT SERINE RESIDUES, AND
RP SUBCELLULAR LOCATION.
RX PubMed=18234692; DOI=10.1093/intimm/dxm154;
RA Muromoto R., Sekine Y., Imoto S., Ikeda O., Okayama T., Sato N.,
RA Matsuda T.;
RT "BART is essential for nuclear retention of STAT3.";
RL Int. Immunol. 20:395-403(2008).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-727, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-727, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [33]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [34]
RP INTERACTION WITH FER, AND PHOSPHORYLATION BY FER.
RX PubMed=19147545; DOI=10.1158/1541-7786.MCR-08-0117;
RA Zoubeidi A., Rocha J., Zouanat F.Z., Hamel L., Scarlata E.,
RA Aprikian A.G., Chevalier S.;
RT "The Fer tyrosine kinase cooperates with interleukin-6 to activate
RT signal transducer and activator of transcription 3 and promote human
RT prostate cancer cell growth.";
RL Mol. Cancer Res. 7:142-155(2009).
RN [35]
RP INTERACTION WITH BIRC5/SURVIVIN.
RX PubMed=20826784; DOI=10.1074/jbc.M110.152777;
RA Wang H., Holloway M.P., Ma L., Cooper Z.A., Riolo M., Samkari A.,
RA Elenitoba-Johnson K.S., Chin Y.E., Altura R.A.;
RT "Acetylation directs survivin nuclear localization to repress STAT3
RT oncogenic activity.";
RL J. Biol. Chem. 285:36129-36137(2010).
RN [36]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-727, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [37]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [38]
RP PHOSPHORYLATION AT TYR-705 IN RESPONSE TO KIT SIGNALING, AND
RP PHOSPHORYLATION AT SER-727.
RX PubMed=21135090; DOI=10.1074/jbc.M110.182642;
RA Chaix A., Lopez S., Voisset E., Gros L., Dubreuil P., De Sepulveda P.;
RT "Mechanisms of STAT protein activation by oncogenic KIT mutants in
RT neoplastic mast cells.";
RL J. Biol. Chem. 286:5956-5966(2011).
RN [39]
RP FUNCTION, AND INTERACTION WITH EIF2AK2.
RX PubMed=23084476; DOI=10.1016/j.molcel.2012.09.013;
RA Shen S., Niso-Santano M., Adjemian S., Takehara T., Malik S.A.,
RA Minoux H., Souquere S., Marino G., Lachkar S., Senovilla L.,
RA Galluzzi L., Kepp O., Pierron G., Maiuri M.C., Hikita H., Kroemer R.,
RA Kroemer G.;
RT "Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity.";
RL Mol. Cell 48:667-680(2012).
RN [40]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [41]
RP VARIANTS AD-HIES GLN-382; LEU-382; TRP-382; LEU-384; SER-384; GLN-423;
RP VAL-463 DEL; ASN-611; VAL-621; ILE-622; LEU-637; MET-637; GLN-644 DEL
RP AND CYS-657.
RX PubMed=17881745; DOI=10.1056/NEJMoa073687;
RA Holland S.M., DeLeo F.R., Elloumi H.Z., Hsu A.P., Uzel G., Brodsky N.,
RA Freeman A.F., Demidowich A., Davis J., Turner M.L., Anderson V.L.,
RA Darnell D.N., Welch P.A., Kuhns D.B., Frucht D.M., Malech H.L.,
RA Gallin J.I., Kobayashi S.D., Whitney A.R., Voyich J.M., Musser J.M.,
RA Woellner C., Schaffer A.A., Puck J.M., Grimbacher B.;
RT "STAT3 mutations in the hyper-IgE syndrome.";
RL N. Engl. J. Med. 357:1608-1619(2007).
RN [42]
RP VARIANTS AD-HIES GLN-382; TRP-382; ILE-389; TYR-437 AND VAL-463 DEL,
RP AND CHARACTERIZATION OF VARIANTS AD-HIES GLN-382; TRP-382; ILE-389;
RP TYR-437 AND VAL-463 DEL.
RX PubMed=17676033; DOI=10.1038/nature06096;
RA Minegishi Y., Saito M., Tsuchiya S., Tsuge I., Takada H., Hara T.,
RA Kawamura N., Ariga T., Pasic S., Stojkovic O., Metin A.,
RA Karasuyama H.;
RT "Dominant-negative mutations in the DNA-binding domain of STAT3 cause
RT hyper-IgE syndrome.";
RL Nature 448:1058-1062(2007).
CC -!- FUNCTION: Signal transducer and transcription activator that
CC mediates cellular responses to interleukins, KITLG/SCF and other
CC growth factors. May mediate cellular responses to activated FGFR1,
CC FGFR2, FGFR3 and FGFR4. Binds to the interleukin-6 (IL-6)-
CC responsive elements identified in the promoters of various acute-
CC phase protein genes. Activated by IL31 through IL31RA. Cytoplasmic
CC STAT3 represses macroautophagy by inhibiting EIF2AK2/PKR activity.
CC Plays an important role in host defense in methicillin-resistant
CC S.aureus lung infection by regulating the expression of the
CC antimicrobial lectin REG3G (By similarity).
CC -!- SUBUNIT: Forms a homodimer or a heterodimer with a related family
CC member (at least STAT1). Interacts with IL31RA, NCOA1, PELP1,
CC SIPAR, SOCS7, STATIP1 and TMF1. Interacts with HCV core protein.
CC Interacts with IL23R in presence of IL23. Interacts (via SH2
CC domain) with NLK. Interacts with ARL2BP; the interaction is
CC enhanced by LIF and JAK1 expression (By similarity). Interacts
CC with KPNA4 and KPNA5; KPNA4 may be the primary mediator of nuclear
CC import (By similarity). Interacts with CAV2; the interaction is
CC increased on insulin-induced tyrosine phosphorylation of CAV2 and
CC leads to STAT3 activation (By similarity). Interacts with ARL2BP;
CC interaction is enhanced with ARL2. Interacts with NEK6 (By
CC similarity). Binds to CDK9 when activated and nuclear. Interacts
CC with BMX. Interacts with ZIPK/DAPK3. Interacts with PIAS3; the
CC interaction occurs on stimulation by IL6, CNTF or OSM and inhibits
CC the DNA binding activity of STAT3. In prostate cancer cells,
CC interacts with STAT3 and promotes DNA binding activity of STAT3.
CC Interacts with STMN3, antagonizing its microtubule-destabilizing
CC activity. Interacts with the 'Lys-129' acetylated form of
CC BIRC5/survivin. Interacts with FER. Interacts (via SH2 domain)
CC with EIF2AK2/PKR (via the kinase catalytic domain).
CC -!- INTERACTION:
CC Q9DUM3:- (xeno); NbExp=4; IntAct=EBI-518675, EBI-7971837;
CC O14874:BCKDK; NbExp=2; IntAct=EBI-518675, EBI-1046765;
CC Q96G01:BICD1; NbExp=2; IntAct=EBI-518675, EBI-1104509;
CC P07384:CAPN1; NbExp=2; IntAct=EBI-518675, EBI-1542113;
CC P31146:CORO1A; NbExp=2; IntAct=EBI-518675, EBI-1046676;
CC Q99062:CSF3R; NbExp=4; IntAct=EBI-518675, EBI-7331284;
CC Q9UER7:DAXX; NbExp=4; IntAct=EBI-518675, EBI-77321;
CC O95661:DIRAS3; NbExp=3; IntAct=EBI-518675, EBI-6139214;
CC Q13011:ECH1; NbExp=2; IntAct=EBI-518675, EBI-711968;
CC P30084:ECHS1; NbExp=3; IntAct=EBI-518675, EBI-719602;
CC P00533:EGFR; NbExp=5; IntAct=EBI-518675, EBI-297353;
CC P04626:ERBB2; NbExp=9; IntAct=EBI-518675, EBI-641062;
CC Q15910:EZH2; NbExp=5; IntAct=EBI-518675, EBI-530054;
CC Q8TAE8:GADD45GIP1; NbExp=4; IntAct=EBI-518675, EBI-372506;
CC Q9BVP2:GNL3; NbExp=2; IntAct=EBI-518675, EBI-641642;
CC Q07666:KHDRBS1; NbExp=2; IntAct=EBI-518675, EBI-1364;
CC O43318:MAP3K7; NbExp=4; IntAct=EBI-518675, EBI-358684;
CC P45984:MAPK9; NbExp=2; IntAct=EBI-518675, EBI-713568;
CC P45984-1:MAPK9; NbExp=3; IntAct=EBI-518675, EBI-713586;
CC Q8TE76:MORC4; NbExp=2; IntAct=EBI-518675, EBI-3940432;
CC Q92665:MRPS31; NbExp=2; IntAct=EBI-518675, EBI-720602;
CC P22736:NR4A1; NbExp=3; IntAct=EBI-518675, EBI-721550;
CC Q9ULD0:OGDHL; NbExp=2; IntAct=EBI-518675, EBI-3940481;
CC P06401:PGR; NbExp=3; IntAct=EBI-518675, EBI-78539;
CC P18031:PTPN1; NbExp=2; IntAct=EBI-518675, EBI-968788;
CC Q04206:RELA; NbExp=4; IntAct=EBI-518675, EBI-73886;
CC P46781:RPS9; NbExp=2; IntAct=EBI-518675, EBI-351206;
CC O00570:SOX1; NbExp=2; IntAct=EBI-518675, EBI-2935583;
CC P30626:SRI; NbExp=2; IntAct=EBI-518675, EBI-750459;
CC Q06520:SULT2A1; NbExp=2; IntAct=EBI-518675, EBI-3921363;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Shuttles between
CC the nucleus and the cytoplasm. Translocated into the nucleus upon
CC tyrosine phosphorylation and dimerization, in response to
CC signaling by activated FGFR1, FGFR2, FGFR3 or FGFR4. Constitutive
CC nuclear presence is independent of tyrosine phosphorylation.
CC Predominantly present in the cytoplasm without stimuli. Upon
CC leukemia inhibitory factor (LIF) stimulation, accumulates in the
CC nucleus. The complex composed of BART and ARL2 plays an important
CC role in the nuclear translocation and retention of STAT3.
CC Identified in a complex with LYN and PAG1.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P40763-1; Sequence=Displayed;
CC Name=Del-701;
CC IsoId=P40763-2; Sequence=VSP_010474;
CC Note=Contains a phosphotyrosine at position 704;
CC -!- TISSUE SPECIFICITY: Heart, brain, placenta, lung, liver, skeletal
CC muscle, kidney and pancreas.
CC -!- PTM: Tyrosine phosphorylated upon stimulation with EGF. Tyrosine
CC phosphorylated in response to constitutively activated FGFR1,
CC FGFR2, FGFR3 and FGFR4 (By similarity). Activated through tyrosine
CC phosphorylation by BMX. Tyrosine phosphorylated in response to
CC IL6, IL11, LIF, CNTF, KITLG/SCF, CSF1, EGF, PDGF, IFN-alpha and
CC OSM. Activated KIT promotes phosphorylation on tyrosine residues
CC and subsequent translocation to the nucleus. Phosphorylated on
CC serine upon DNA damage, probably by ATM or ATR. Serine
CC phosphorylation is important for the formation of stable DNA-
CC binding STAT3 homodimers and maximal transcriptional activity.
CC ARL2BP may participate in keeping the phosphorylated state of
CC STAT3 within the nucleus. Upon LPS challenge, phosphorylated
CC within the nucleus by IRAK1. Upon erythropoietin treatment,
CC phosphorylated on Ser-727 by RPS6KA5. Phosphoryation at Tyr-705 by
CC PTK6 or FER leads to an increase of its transcriptional activity.
CC Dephosphorylation on tyrosine residues by PTPN2 negatively
CC regulates IL6/interleukin-6 signaling.
CC -!- DISEASE: Hyperimmunoglobulin E recurrent infection syndrome,
CC autosomal dominant (AD-HIES) [MIM:147060]: A rare disorder of
CC immunity and connective tissue characterized by immunodeficiency,
CC chronic eczema, recurrent Staphylococcal infections, increased
CC serum IgE, eosinophilia, distinctive coarse facial appearance,
CC abnormal dentition, hyperextensibility of the joints, and bone
CC fractures. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- MISCELLANEOUS: Involved in the gp130-mediated signaling pathway.
CC -!- SIMILARITY: Belongs to the transcription factor STAT family.
CC -!- SIMILARITY: Contains 1 SH2 domain.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=STAT3 entry;
CC URL="http://en.wikipedia.org/wiki/STAT3";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/STAT3ID444.html";
CC -!- WEB RESOURCE: Name=STAT3base; Note=STAT3 mutation db;
CC URL="http://bioinf.uta.fi/STAT3base/";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/stat3/";
CC -----------------------------------------------------------------------
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DR EMBL; L29277; AAA58374.1; -; mRNA.
DR EMBL; AJ012463; CAA10032.1; -; mRNA.
DR EMBL; AY572796; AAS66986.1; -; Genomic_DNA.
DR EMBL; AK291933; BAF84622.1; -; mRNA.
DR EMBL; BC000627; AAH00627.1; -; mRNA.
DR EMBL; BC014482; AAH14482.1; -; mRNA.
DR EMBL; AF029311; AAB84254.1; -; mRNA.
DR PIR; A54444; A54444.
DR RefSeq; NP_003141.2; NM_003150.3.
DR RefSeq; NP_644805.1; NM_139276.2.
DR RefSeq; NP_998827.1; NM_213662.1.
DR UniGene; Hs.463059; -.
DR ProteinModelPortal; P40763; -.
DR SMR; P40763; 2-715.
DR DIP; DIP-33584N; -.
DR IntAct; P40763; 83.
DR MINT; MINT-146801; -.
DR STRING; 9606.ENSP00000264657; -.
DR BindingDB; P40763; -.
DR ChEMBL; CHEMBL4026; -.
DR PhosphoSite; P40763; -.
DR DMDM; 48429227; -.
DR PaxDb; P40763; -.
DR PeptideAtlas; P40763; -.
DR PRIDE; P40763; -.
DR DNASU; 6774; -.
DR Ensembl; ENST00000264657; ENSP00000264657; ENSG00000168610.
DR Ensembl; ENST00000404395; ENSP00000384943; ENSG00000168610.
DR Ensembl; ENST00000588969; ENSP00000467985; ENSG00000168610.
DR GeneID; 6774; -.
DR KEGG; hsa:6774; -.
DR UCSC; uc002hzk.1; human.
DR CTD; 6774; -.
DR GeneCards; GC17M040465; -.
DR HGNC; HGNC:11364; STAT3.
DR HPA; CAB003859; -.
DR HPA; HPA001671; -.
DR MIM; 102582; gene.
DR MIM; 147060; phenotype.
DR neXtProt; NX_P40763; -.
DR Orphanet; 2314; Autosomal dominant hyper IgE syndrome.
DR PharmGKB; PA337; -.
DR eggNOG; NOG303257; -.
DR HOGENOM; HOG000220792; -.
DR HOVERGEN; HBG055669; -.
DR InParanoid; P40763; -.
DR KO; K04692; -.
DR OMA; NKESHAT; -.
DR OrthoDB; EOG73JKTT; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P40763; -.
DR ChiTaRS; STAT3; human.
DR GeneWiki; STAT3; -.
DR GenomeRNAi; 6774; -.
DR NextBio; 26438; -.
DR PMAP-CutDB; P40763; -.
DR PRO; PR:P40763; -.
DR ArrayExpress; P40763; -.
DR Bgee; P40763; -.
DR CleanEx; HS_STAT3; -.
DR Genevestigator; P40763; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0004879; F:ligand-activated sequence-specific DNA binding RNA polymerase II transcription factor activity; IDA:BHF-UCL.
DR GO; GO:0046983; F:protein dimerization activity; ISS:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; ISS:UniProtKB.
DR GO; GO:0043565; F:sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0004871; F:signal transducer activity; TAS:ProtInc.
DR GO; GO:0044212; F:transcription regulatory region DNA binding; IDA:BHF-UCL.
DR GO; GO:0006953; P:acute-phase response; IEA:Ensembl.
DR GO; GO:0048708; P:astrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0008283; P:cell proliferation; IEA:Ensembl.
DR GO; GO:0006928; P:cellular component movement; TAS:ProtInc.
DR GO; GO:0042755; P:eating behavior; ISS:UniProtKB.
DR GO; GO:0001754; P:eye photoreceptor cell differentiation; ISS:UniProtKB.
DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB.
DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0060397; P:JAK-STAT cascade involved in growth hormone signaling pathway; ISS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; TAS:ProtInc.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0016310; P:phosphorylation; ISS:UniProtKB.
DR GO; GO:0045747; P:positive regulation of Notch signaling pathway; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0006606; P:protein import into nucleus; IDA:UniProtKB.
DR GO; GO:0060019; P:radial glial cell differentiation; ISS:UniProtKB.
DR GO; GO:0040014; P:regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0032355; P:response to estradiol stimulus; IDA:BHF-UCL.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0019953; P:sexual reproduction; ISS:UniProtKB.
DR GO; GO:0019827; P:stem cell maintenance; IEA:Ensembl.
DR GO; GO:0001659; P:temperature homeostasis; ISS:UniProtKB.
DR Gene3D; 1.10.238.10; -; 1.
DR Gene3D; 1.10.532.10; -; 1.
DR Gene3D; 1.20.1050.20; -; 1.
DR Gene3D; 2.60.40.630; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR011992; EF-hand-dom_pair.
DR InterPro; IPR008967; p53-like_TF_DNA-bd.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR001217; STAT.
DR InterPro; IPR013800; STAT_TF_alpha.
DR InterPro; IPR015988; STAT_TF_coiled-coil.
DR InterPro; IPR013801; STAT_TF_DNA-bd.
DR InterPro; IPR012345; STAT_TF_DNA-bd_sub.
DR InterPro; IPR013799; STAT_TF_prot_interaction.
DR PANTHER; PTHR11801; PTHR11801; 1.
DR Pfam; PF00017; SH2; 1.
DR Pfam; PF01017; STAT_alpha; 1.
DR Pfam; PF02864; STAT_bind; 1.
DR Pfam; PF02865; STAT_int; 1.
DR SMART; SM00252; SH2; 1.
DR SMART; SM00964; STAT_int; 1.
DR SUPFAM; SSF47655; SSF47655; 1.
DR SUPFAM; SSF48092; SSF48092; 1.
DR SUPFAM; SSF49417; SSF49417; 1.
DR PROSITE; PS50001; SH2; 1.
PE 1: Evidence at protein level;
KW Activator; Alternative splicing; Complete proteome; Cytoplasm;
KW Disease mutation; DNA-binding; Host-virus interaction; Nucleus;
KW Phosphoprotein; Polymorphism; Reference proteome; SH2 domain;
KW Transcription; Transcription regulation.
FT CHAIN 1 770 Signal transducer and activator of
FT transcription 3.
FT /FTId=PRO_0000182417.
FT DOMAIN 580 670 SH2.
FT MOTIF 150 162 Essential for nuclear import.
FT MOD_RES 705 705 Phosphotyrosine; by FER and PTK6.
FT MOD_RES 727 727 Phosphoserine; by DYRK2, NLK, NEK6,
FT IRAK1, RPS6KA5, ZIPK/DAPK3 and PKC/PRKCE.
FT VAR_SEQ 701 701 Missing (in isoform Del-701).
FT /FTId=VSP_010474.
FT VARIANT 32 32 Q -> K (in dbSNP:rs1803125).
FT /FTId=VAR_018683.
FT VARIANT 143 143 M -> I (in dbSNP:rs17878478).
FT /FTId=VAR_018679.
FT VARIANT 382 382 R -> L (in AD-HIES).
FT /FTId=VAR_037365.
FT VARIANT 382 382 R -> Q (in AD-HIES; loss of function).
FT /FTId=VAR_037366.
FT VARIANT 382 382 R -> W (in AD-HIES; loss of function).
FT /FTId=VAR_037367.
FT VARIANT 384 384 F -> L (in AD-HIES).
FT /FTId=VAR_037368.
FT VARIANT 384 384 F -> S (in AD-HIES).
FT /FTId=VAR_037369.
FT VARIANT 389 389 T -> I (in AD-HIES; loss of function).
FT /FTId=VAR_037370.
FT VARIANT 423 423 R -> Q (in AD-HIES).
FT /FTId=VAR_037371.
FT VARIANT 437 437 H -> Y (in AD-HIES; loss of function).
FT /FTId=VAR_037372.
FT VARIANT 463 463 Missing (in AD-HIES; loss of function).
FT /FTId=VAR_037373.
FT VARIANT 561 561 F -> Y (in dbSNP:rs1064116).
FT /FTId=VAR_037374.
FT VARIANT 611 611 S -> N (in AD-HIES).
FT /FTId=VAR_037375.
FT VARIANT 621 621 F -> V (in AD-HIES).
FT /FTId=VAR_037376.
FT VARIANT 622 622 T -> I (in AD-HIES).
FT /FTId=VAR_037377.
FT VARIANT 637 637 V -> L (in AD-HIES).
FT /FTId=VAR_037378.
FT VARIANT 637 637 V -> M (in AD-HIES).
FT /FTId=VAR_037379.
FT VARIANT 644 644 Missing (in AD-HIES).
FT /FTId=VAR_037380.
FT VARIANT 657 657 Y -> C (in AD-HIES).
FT /FTId=VAR_037381.
FT CONFLICT 133 133 T -> A (in Ref. 4; BAF84622).
FT CONFLICT 288 288 Q -> H (in Ref. 1; AAA58374).
FT CONFLICT 460 460 P -> S (in Ref. 1; AAA58374).
FT CONFLICT 548 548 K -> N (in Ref. 1; AAA58374).
FT CONFLICT 652 652 E -> V (in Ref. 4; BAF84622).
FT CONFLICT 667 667 V -> L (in Ref. 1; AAA58374).
FT CONFLICT 730 730 T -> A (in Ref. 1; AAA58374).
SQ SEQUENCE 770 AA; 88068 MW; 6C00632211C8012D CRC64;
MAQWNQLQQL DTRYLEQLHQ LYSDSFPMEL RQFLAPWIES QDWAYAASKE SHATLVFHNL
LGEIDQQYSR FLQESNVLYQ HNLRRIKQFL QSRYLEKPME IARIVARCLW EESRLLQTAA
TAAQQGGQAN HPTAAVVTEK QQMLEQHLQD VRKRVQDLEQ KMKVVENLQD DFDFNYKTLK
SQGDMQDLNG NNQSVTRQKM QQLEQMLTAL DQMRRSIVSE LAGLLSAMEY VQKTLTDEEL
ADWKRRQQIA CIGGPPNICL DRLENWITSL AESQLQTRQQ IKKLEELQQK VSYKGDPIVQ
HRPMLEERIV ELFRNLMKSA FVVERQPCMP MHPDRPLVIK TGVQFTTKVR LLVKFPELNY
QLKIKVCIDK DSGDVAALRG SRKFNILGTN TKVMNMEESN NGSLSAEFKH LTLREQRCGN
GGRANCDASL IVTEELHLIT FETEVYHQGL KIDLETHSLP VVVISNICQM PNAWASILWY
NMLTNNPKNV NFFTKPPIGT WDQVAEVLSW QFSSTTKRGL SIEQLTTLAE KLLGPGVNYS
GCQITWAKFC KENMAGKGFS FWVWLDNIID LVKKYILALW NEGYIMGFIS KERERAILST
KPPGTFLLRF SESSKEGGVT FTWVEKDISG KTQIQSVEPY TKQQLNNMSF AEIIMGYKIM
DATNILVSPL VYLYPDIPKE EAFGKYCRPE SQEHPEADPG SAAPYLKTKF ICVTPTTCSN
TIDLPMSPRT LDSLMQFGNN GEGAEPSAGG QFESLTFDME LTSECATSPM
//

MIM 102582
*RECORD*
*FIELD* NO
102582
*FIELD* TI
*102582 SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3; STAT3
;;ACUTE-PHASE RESPONSE FACTOR; APRF
read more*FIELD* TX

CLONING

Akira et al. (1994) purified acute-phase response factor (APRF), also
designated STAT3, and cloned the cDNA. At the amino acid level, APRF
exhibited 52.5% overall homology with p91, a component of the interferon
(IFN)-stimulated gene factor-3 complexes. Also see STAT1 (600555).

Caldenhoven et al. (1996) reported the cloning of a cDNA encoding a
variant of the transcription factor STAT3, designated STAT3-beta, that
was isolated by screening an eosinophil cDNA library. Compared to
wildtype STAT3, STAT3-beta lacks an internal domain of 50 bp located
near the C terminus. This splice product is a naturally occurring
isoform of STAT3 and encodes an 80-kD protein.

Using Northern blot analysis, Miyoshi et al. (2001) detected expression
of a 5.0-kb mouse Stat3 transcript that was highest in liver and heart,
intermediate in lung, spleen, brain, testis, and kidney, and lowest in
muscle.

GENE STRUCTURE

Miyoshi et al. (2001) determined that the mouse Stat3 gene contains 24
exons and spans 30 kb. The translation initiation codon is in exon 2,
and the stop codon is in exon 24. The gene has a single promoter.

MAPPING

Choi et al. (1996) used fluorescence in situ hybridization to map the
STAT3 gene to chromosome 17q21.

Miyoshi et al. (2001) determined that the mouse Stat3 and Stat5a
(601511) genes are located next to each other in a tail-to-tail
orientation on chromosome 11, with their polyadenylation sites 3.0 kb
apart. The order and orientation of genes at this locus, Ptrf
(603198)--Stat3--Stat5a--Stat5b (604260)--Lgp1 (608587)--Hcrt (602358),
are identical in the region of syntenic homology on human chromosome
17q21.

GENE FUNCTION

Acute-phase response factor is a latent cytoplasmic transcription factor
that is rapidly activated in response to interleukin-5 (IL5; 147850),
interleukin-6 (IL6; 147620), epidermal growth factor (131530), leukemia
inhibitory factor (159540), oncostatin M (165095), interleukin-11
(147681), and ciliary neurotrophic factor (118945). After activation,
the 89-kD protein binds to IL6 response elements identified in the
promoter regions of various IL6-induced plasma-protein and
intermediate-early genes. Lutticken et al. (1994) demonstrated that the
above listed cytokines cause tyrosine phosphorylation of the APRF.
Protein kinases of the JAK family (e.g., 147795) were also rapidly
tyrosine phosphorylated, and both APRF and JAK1 associated with the
signal transducer gp130 (IL6ST; 600694). Akira et al. (1994) suggested
that APRF may play a major role in the gp130-mediated signaling pathway.

Binding of IL5 to its specific receptor activates JAK2 (147796) which
leads to the tyrosine phosphorylation of STAT3 proteins. Caldenhoven et
al. (1996) found that STAT3-beta, like STAT3, is phosphorylated on
tyrosine and binds to the pIRE from the ICAM1 (147840) promoter after
IL5 stimulation. Coexpression of STAT3-beta inhibits the transactivation
potential of STAT3. These results suggested that STAT3-beta functions as
a negative regulator of transcription.

The leptin receptor (601007) is found in many tissues in several
alternatively spliced forms, raising the possibility that leptin
(164160) exerts effects on many tissues including the hypothalamus. The
leptin receptor is a member of the gp130 family of cytokine receptors
that are known to stimulate gene transcription via activation of
cytosolic STAT proteins. In order to identify the sites of leptin action
in vivo, Vaisse et al. (1996) assayed for activation of STAT proteins in
mice treated with leptin. The STAT proteins bind to phosphotyrosine
residues in the cytoplasmic domain of the ligand-activated receptor,
where they are subsequently phosphorylated. The activated STAT proteins
dimerize and translocate to the nucleus, where they bind DNA and
activate transcription. The investigators assayed the activation of STAT
proteins in response to leptin in a variety of mouse tissues known to
express the leptin receptor, Obr. Leptin injection activated Stat3 but
no other STAT protein in the hypothalamus of ob/ob and wildtype mice but
not db/db mice, mutants that lack an isoform of the leptin receptor.
Leptin did not induce STAT activation in any of the other tissues
tested. The dose-dependent activation of STAT3 by leptin was first
observed after 15 minutes and later at 30 minutes. The data indicated to
Vaisse et al. (1996) that the hypothalamus is a direct target of leptin
action and this activation is critically dependent on the gp130-like
leptin receptor isoform missing in db/db mice.

Pfeffer et al. (1997) found that STAT3, a transcription factor for acute
phase response genes, acts as an adaptor molecule in signal transduction
from the type I interferon receptor. They found that it binds to a
conserved sequence in the cytoplasmic tail of the IFNAR1 (107450) chain
of the receptor and undergoes interferon-dependent tyrosine
phosphorylation. The p85 regulatory subunit of phosphatidylinositol
3-kinase, which activates a series of serine kinases, was found to bind
to phosphorylated STAT3 and subsequently to undergo tyrosine
phosphorylation. The authors concluded that STAT3 acts as an adaptor to
couple another signaling pathway to the interferon receptor.

The cytokines LIF (159540) and BMP2 (112261) signal through different
receptors and transcription factors, namely STATs and SMADs,
respectively. Nakashima et al. (1999) found that LIF and BMP2 act in
synergy on primary fetal neural progenitor cells to induce astrocytes.
The transcriptional coactivator p300 (602700) interacted physically with
STAT3 at its amino terminus in a cytokine stimulation-independent
manner, and with SMAD1 (601595) at its carboxyl terminus in a cytokine
stimulation-dependent manner. The formation of a complex between STAT3
and SMAD1, bridged by p300, is involved in the cooperative signaling of
LIF and BMP2 and the subsequent induction of astrocytes from neuronal
progenitors.

Foley et al. (2002) demonstrated that synthesis of STAT3-beta by
erythroleukemia and primary erythroid progenitor cells treated with IL6
silences gamma-globin expression. They identified the STAT3-like binding
sequence in both the A-gamma (142200) and G-gamma (142250) promoters.

Ram et al. (2000) studied the roles of the MAP kinases (see MAPK1,
176948) and STAT3 in transformation of NIH 3T3 cells by Q205L Go-alpha
(see 139311). Expression of Q205L Go-alpha in NIH 3T3 cells activated
STAT3. Coexpression of dominant-negative STAT3 inhibited Q205L
Go-alpha-induced transformation of NIH 3T3 cells and activation of
endogenous STAT3. Ram et al. (2000) concluded that STAT3 can function as
a downstream effector for Q205L Go-alpha and mediate its biologic
effects.

In many human cancers and transformed cell lines, STAT3 is persistently
activated, and in cell culture, active STAT3 is either required for
transformation, enhances transformation, or blocks apoptosis. Bromberg
et al. (1999) reported that substitution of 2 cysteine residues within
the C-terminal loop of the SH2 domain of the murine Stat3 gene produced
a molecule that dimerized spontaneously, bound to DNA, and activated
transcription. In immortalized fibroblasts, this mutant Stat3 molecule
caused cellular transformation scored by colony formation in soft agar
and tumor formation in nude mice. Thus, the authors concluded that the
activated STAT3 molecule by itself can mediate cellular transformation,
and the experiments focused attention on the importance of constitutive
STAT3 activation in human tumors.

STAT proteins become phosphorylated on tyrosine and translocate to the
nucleus after stimulation of cells with growth factors or cytokines.
Simon et al. (2000) showed that the RAC1 guanosine triphosphatase
(602048) can bind to and regulate STAT3 activity. Dominant-negative RAC1
inhibited STAT3 activation by growth factors, whereas activated RAC1
stimulated STAT3 phosphorylation on both tyrosine and serine residues.
Moreover, activated RAC1 formed a complex with STAT3 in mammalian cells.
Yeast 2-hybrid analysis indicated that STAT3 binds directly to active
but not inactive RAC1 and that the interaction occurs via the effector
domain. Simon et al. (2000) concluded that RAC1 may serve as an
alternative mechanism for targeting STAT3 to tyrosine kinase signaling
complexes.

Chung et al. (1997) identified PIAS3 (605987) as an inhibitor of STAT3
signaling.

Using transient transfection methods, Scoles et al. (2002) showed that
both schwannomin (NF2; 607379) and human growth factor-regulated
tyrosine kinase substrate HRS (HGS; 604375) inhibited STAT3 activation,
and that schwannomin suppressed STAT3 activation mediated by IGF1
(147440) treatment in a human schwannoma cell line. Schwannomin
inhibited STAT3 and STAT5 (601511) phosphorylation in a rat schwannoma
cell line. Schwannomin with the pathogenic missense mutation Q538P
(607379.0006) failed to bind HRS and did not inhibit STAT5
phosphorylation. The authors hypothesized that schwannomin requires HRS
interaction to be fully functionally active and to inhibit STAT
activation.

Tyr1138 of the leptin receptor long form (LRb; see 601007) mediates
activation of the transcription factor STAT3 during leptin (164160)
action. To investigate the contribution of STAT3 signaling to leptin
action in vivo, Bates et al. (2003) replaced the gene encoding the
leptin receptor (Lepr) in mice with an allele coding for replacement of
tyr1138 in LRb with a serine residue that specifically disrupts the
LRb-STAT3 signal. Like db/db mice, Lepr(S1138) homozygotes (s/s) are
hyperphagic and obese. However, whereas db/db mice are infertile, short,
and diabetic, s/s mice are fertile, long, and less hyperglycemic.
Furthermore, hypothalamic expression of neuropeptide Y (NPY; 162640) is
elevated in db/db mice but not in s/s mice, whereas the hypothalamic
melanocortin system is suppressed in both db/db and s/s mice. Bates et
al. (2003) concluded that LRb-STAT3 signaling mediates the effects of
leptin on melanocortin production and body energy homeostasis, whereas
distinct LRb signals regulate NPY and the control of fertility, growth,
and glucose homeostasis.

Using wildtype STAT3 and an activation mutant, STAT3(Y705F),
Bhattacharya and Schindler (2003) demonstrated the existence of a basal
nuclear export pathway independent of tyrosine phosphorylation and, by
extension, implied the existence of a basal nuclear import pathway. They
identified 3 nuclear export signal (NES) elements, 1 involved in
poststimulation export and 2 that regulate basal nuclear export, and
concluded that STAT3 nuclear export is dependent on multiple NES
elements.

Zhang et al. (2003) stated that phosphorylation of ser727 is required
for STAT3 activation by diverse stimuli, including ultraviolet (UV)
irradiation. They presented evidence that phosphorylation of ser727
involves a signaling pathway that includes ATM (607585), MAPKs, and RSK2
(300075), as well as other downstream kinases or cofactors. In addition,
RSK2-mediated ser727 phosphorylation was required for basal and
UV-stimulated STAT3 transcriptional activities.

Lovato et al. (2003) found that STAT3 and STAT4 (600558) were
constitutively activated in intestinal T cells from Crohn disease
patients (see IBD22, 612380), but not in healthy volunteers. Other STAT
proteins were not constitutively activated. The STAT3-regulated protein
SOCS3 (604176) was also constitutively expressed in Crohn disease T
cells. Lovato et al. (2003) concluded that there is abnormal STAT/SOCS
signaling in Crohn disease.

Yuan et al. (2005) showed that in response to cytokine treatment, STAT3
is acetylated on a single lysine residue, lys685. Histone
acetyltransferase p300 (602700)-mediated STAT3 acetylation on lys685 was
reversible by type I histone deacetylase (see 605314). Using a prostate
cancer cell line that lacks STAT3, they established cell lines
expressing wildtype STAT3 or a STAT3 mutant containing a lys685-to-arg
substitution. Their findings showed that lys685 acetylation was critical
for STAT3 to form stable dimers required for cytokine-stimulated DNA
binding and transcriptional regulation, to enhance transcription of cell
growth-related genes, and to promote cell cycle progression in response
to treatment with oncostatin M (165095).

McLoughlin et al. (2005) showed that Il6 -/- mice with Staphylococcus
epidermidis-induced peritoneal inflammation exhibited impaired T-cell
recruitment with reduced expression of chemokine receptors (e.g., CCR5;
601373) and defective expression of chemokines (e.g., CCL4; 182284).
Experiments with knockin mice expressing mutated forms of gp130 (IL6ST;
600694) indicated that Il6-mediated T-cell recruitment required
gp130-dependent Stat3 activation.

Kokoeva et al. (2005) demonstrated that centrally administered ciliary
neurotrophic factor (CNTF; 118945) induces cell proliferation and
feeding centers of the murine hypothalamus. Many of the newborn cells
expressed neuronal markers and showed functional phenotypes relevant for
energy balance control, including the capacity for leptin-induced
phosphorylation of STAT3. Coadministration of the mitotic blocker Ara-C
eliminated the proliferation of neural cells and abrogated the
long-term, but not the short-term, effect of CNTF on body weight.
Kokoeva et al. (2005) concluded that their findings link the sustained
effect of CNTF on energy balance to hypothalamic neurogenesis.

T-cell lymphomas lose expression of SHP1 (PTPN6; 176883) due to DNA
methylation of its promoter. Zhang et al. (2005) demonstrated that
malignant T cells expressed DNMT1 (126375) and that STAT3 could bind
sites in the SHP1 promoter in vitro. STAT3, DNMT1, and HDAC1 (601241)
formed complexes and bound to the SHP1 promoter in vivo. Antisense DNMT1
and STAT3 siRNA induced DNA demethylation in malignant T cells and
expression of SHP1. Zhang et al. (2005) concluded that STAT3 may
transform cells by inducing epigenetic silencing of SHP1 in cooperation
with DNMT1 and HDAC1.

Most Toxoplasma gondii isolates in Europe and North America belong to 3
clonal lines, designated types I, II, and III. Using microarray,
immunofluorescence, and Western blot analyses, Saeij et al. (2007) found
that STAT3 and STAT6 (601512) were activated predominantly in
fibroblasts infected with types I and III, rather than type II, T.
gondii. They determined that the T. gondii Rop16 protein kinase mediated
the strain-specific activation of STAT3 and STAT6. Saeij et al. (2007)
noted that their results correlated with previous findings showing that
type II T. gondii induces high levels of IL12A (161560) and IL12B
(161561) secretion, whereas type I T. gondii induces STAT3 activation
and prevents IL12 expression.

Bong et al. (2007) found that vertebrate ephrin B1 (EFNB1; 300035)
interacted with Stat3 in a tyrosine phosphorylation-dependent manner,
resulting in phosphorylation and enhanced transcriptional activation of
Stat3.

Ying et al. (2008) demonstrated that, contrary to long-held belief,
extrinsic stimuli are dispensable for the derivation, propagation, and
pluripotency of embryonic stem (ES) cells. Self-renewal is enabled by
the elimination of differentiation-inducing signaling from
mitogen-activated protein kinase (see 176948). Additional inhibition of
glycogen synthase kinase-3 (see 606784) consolidates biosynthetic
capacity and suppresses residual differentiation. Complete bypass of
cytokine signaling was confirmed by isolating ES cells genetically
devoid of STAT3. Ying et al. (2008) concluded that ES cells have an
innate program for self-replication that does not require extrinsic
instruction. The authors suggested that this property may account for
their latent tumorigenicity.

Bai et al. (2008) investigated the effects of IFNG (147570) on vascular
smooth muscle cells (VSMCs) through interactions involving STAT
proteins. They found that IFNG stimulation phosphorylated both STAT1 and
STAT3 in human VSMCs, but not in mouse VSMCs or human endothelial cells.
Activation by IFNG induced STAT3 translocation to the nucleus.
Microarray analysis identified signaling candidates that were inducible
by IFNG and dependent on STAT3, and RT-PCR and immunoblot analyses
verified roles for XAF1 (606717) and NOXA (PMAIP1; 604959). STAT3
activation sensitized VSMCs to apoptosis triggered by both death
receptor- and mitochondria-mediated pathways. Knockdown of XAF1 and NOXA
expression inhibited priming of VSMCs to apoptotic stimuli by IFNG.
Immunodeficient mice with human coronary artery grafts were susceptible
to the proapoptotic effects of XAF1 and NOXA induced by IFNG. Bai et al.
(2008) concluded that STAT1-independent signaling by IFNG via STAT3
promotes death of VSMCs.

Wegrzyn et al. (2009) provided evidence that Stat3 is present in the
mitochondria of mouse cultured cells and primary tissues, including the
liver and heart. In Stat3-null cells, the activities of complexes I and
II of the electron transport chain were significantly decreased. Wegrzyn
et al. (2009) identified Stat3 mutants that selectively restored the
protein's function as a transcription factor or its functions within the
electron transport chain. In mice that do not express Stat3 in the
heart, there were also selective defects in the activities of complexes
I and II of the electron transport chain. Wegrzyn et al. (2009)
concluded that Stat3 is required for optimal function of the electron
transport chain, which may allow it to orchestrate responses to cellular
homeostasis.

Gough et al. (2009) reported that malignant transformation by activated
Ras (190020.0001) is impaired without STAT3, in spite of the inability
of Ras to drive STAT3 tyrosine phosphorylation or nuclear translocation.
Moreover, STAT3 mutants that cannot be tyrosine-phosphorylated, that are
retained in the cytoplasm, or that cannot bind DNA nonetheless supported
Ras-mediated transformation. Unexpectedly, STAT3 was detected within
mitochondria, and exclusive targeting of STAT3 to mitochondria without
nuclear accumulation facilitated Ras transformation. Mitochondrial STAT3
sustained altered glycolytic and oxidative phosphorylation activities
characteristic of cancer cells. Thus, Gough et al. (2009) concluded
that, in addition to its nuclear transcriptional role, STAT3 regulates a
metabolic function in mitochondria, supporting Ras-dependent malignant
transformation.

Chaudhry et al. (2009) demonstrated that pathogenic IL17
(603149)-producing T-helper cell (Th17) responses in mice are restrained
by CD4+ regulatory cells, or T(regs). This suppression was lost upon
T(reg)-specific ablation of Stat3, a transcription factor critical for
Th17 differentiation, and resulted in the development of a fatal
intestinal inflammation. Chaudhry et al. (2009) concluded that T(regs)
adapt to their environment by engaging distinct effector
response-specific suppression modalities upon activation of STAT
proteins that direct the corresponding class of the immune response.

Carro et al. (2010) used reverse engineering and an unbiased
interrogation of a glioma-specific regulatory network to reveal the
transcriptional module that activates expression of mesenchymal genes in
malignant glioma. Two transcription factors, C/EBP-beta (189965) and
STAT3, emerged as synergistic initiators and master regulators of
mesenchymal transformation. Ectopic coexpression of C/EBP-beta and STAT3
reprogrammed neural stem cells along the aberrant mesenchymal lineage,
whereas elimination of the 2 factors in glioma cells led to collapse of
the mesenchymal signature and reduced tumor aggressiveness. In human
glioma, expression of C/EBP-beta and STAT3 correlated with mesenchymal
differentiation and predicted poor clinical outcome. Carro et al. (2010)
concluded that the activation of a small regulatory module is necessary
and sufficient to initiate and maintain an aberrant phenotypic state in
cancer cells.

Shui et al. (2012) reported an important role for epithelial HVEM
(602746) in innate mucosal defense against pathogenic bacteria. HVEM
enhances immune responses by NF-kappa-B (see 164011)-inducing
kinase-dependent STAT3 activation, which promotes the epithelial
expression of genes important for immunity. During intestinal
Citrobacter rodentium infection, a mouse model for enteropathogenic E.
coli infection, Hvem-null mice showed decreased Stat3 activation,
impaired responses in the colon, higher bacterial burdens, and increased
mortality. Shui et al. (2012) identified the immunoglobulin superfamily
molecule CD160 (604463), expressed predominantly by innate-like
intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for
host protection. Likewise, in pulmonary Streptococcus pneumoniae
infection, HVEM is also required for host defense. Shui et al. (2012)
concluded that their results pinpointed HVEM as an important
orchestrator of mucosal immunity, integrating signals from innate
lymphocytes to induce optimal epithelial Stat3 activation, which
indicated that targeting HVEM with agonists could improve host defense.

MOLECULAR GENETICS

- Hyper-IgE Syndrome

Minegishi et al. (2007) showed that dominant-negative mutations in the
STAT3 gene result in the classic multisystem hyper-IgE syndrome (HIES;
147060), a disorder of both immunity and connective tissue. They found
that 8 of 15 unrelated nonfamilial HIES patients had heterozygous STAT3
mutations (see, e.g., 102582.0001-102582.0003). None of the parents or
sibs of the patients had the mutant allele, suggesting that the 5
different mutations, all of which were located in the STAT3 DNA-binding
domain, occurred de novo. All 5 mutants were nonfunctional by themselves
and showed dominant-negative effects when coexpressed with wildtype
STAT3.

Holland et al. (2007) likewise found mutations in STAT3 in the hyper-IgE
syndrome. They found increased levels of proinflammatory gene
transcripts in unstimulated peripheral blood neutrophils and mononuclear
cells from patients with HIES as compared with levels in control cells.
In vitro cultures of mononuclear cells from patients that were
stimulated with lipopolysaccharide had higher tumor necrosis
factor-alpha (TNFA; 191160) levels than did identically treated cells
from unaffected individuals. In contrast, the cells from patients with
HIES generated lower levels of monocyte chemoattractant protein-1 (MCP1;
158105) in response to the presence of interleukin-6, suggesting a
defect in interleukin-6 signaling through its downstream mediators, one
of which is STAT3. Holland et al. (2007) identified missense mutations
and single-codon in-frame deletions in STAT3 in 50 familial and sporadic
cases of HIES. Eighteen discrete mutations, 5 of which were hotspots,
were predicted to affect directly the DNA-binding and SRC homology-2
(SH2) domains.

By flow cytometric and RT-PCR analyses, Ma et al. (2008) demonstrated
that HIES patients with heterozygous mutations in STAT3 failed to
generate IL17-secreting Th17 cells in vivo and in vitro due to a failure
to express sufficient levels of the Th17-specific transcription factor
RORGT (602943). Ma et al. (2008) proposed that, because Th17 cells are
important in immunity against fungal infections, susceptibility to
infections in patients with HIES may be explained by their diminished
ability to generate Th17 cells.

By flow cytometric analysis following mitogen activation of
IL17-expressing blood T cells from healthy controls or patients with
particular genetic traits affecting various cytokine signaling pathways,
de Beaucoudrey et al. (2008) found that there was considerable
interindividual variability in IL17 expression in controls and most
patient groups. However, dominant-negative mutations in STAT3 in HIES
patients and, to a lesser extent, null mutations in IL12B or IL12RB1
(601604) in patients with mendelian susceptibility to mycobacterial
disease (209950) impaired development of IL17-producing T cells.

Using flow cytometric analysis, Siegel et al. (2011) demonstrated a
significant reduction in central memory (i.e., expressing CD27, 186711,
and CD45RO, 151460) CD4 (186940)-positive and CD8 (see 186910)-positive
T cells in autosomal dominant HIES patients that was not due to
apoptosis or cell turnover. Stimulation of naive T cells in the presence
of IL7 (146660) or IL15 (600554) failed to restore memory cell
generation in HIES patients. Impaired differentiation was associated
with decreased expression of 2 STAT3-responsive transcription factors,
BCL6 (109565) and SOCS3 (604176). Siegel et al. (2011) found that HIES
patients had increased risk for reactivation of varicella zoster that
was associated with poor CD4-positive T-cell responses. HIES patients
also had greater detectable Epstein-Barr virus (EBV) viremia that was
associated with compromised T-cell memory to EBV. Siegel et al. (2011)
concluded that STAT3 has a specific role in central memory T-cell
formation.

Crosby et al. (2012) described a patient with food allergies, a high
score for HIES, and eosinophilic esophagitis. They identified a
thr389-to-ile (T389I; 102582.0007) mutation in the patient's STAT3 gene.

- Somatic Mutations in Large Granular Lymphocytic Leukemia

T-cell large granular lymphocytic leukemia is a rare lymphoproliferative
disorder characterized by the expansion of clonal CD3+CD8+ cytotoxic T
lymphocytes (CTLs) and often associated with autoimmune disorders and
immune-mediated cytopenias (summary by Koskela et al., 2012). Koskela et
al. (2012) used next-generation exome sequencing to identify somatic
mutations in CTLs from an index patient with large granular lymphocytic
leukemia and used targeted resequencing in a well-characterized cohort
of 76 patients with this disorder. Mutations in STAT3 were found in 31
of 77 patients (40%) with large granular lymphocytic leukemia. Among
these 31 patients, recurrent mutational hotspots included Y640F in 13
(17%), D661V in 7 (9%), D661Y in 7 (9%), and N647I in 3 (4%). All
mutations were located in exon 21, encoding the Src homology-2 (SH2)
domain, which mediates the dimerization and activation of STAT protein.
The amino acid changes resulted in a more hydrophobic protein surface
and were associated with phosphorylation of STAT3 and its localization
in the nucleus. In vitro functional studies showed that the Y640F and
D661V mutations increased the transcriptional activity of STAT3. In the
affected patients, downstream target genes of the STAT3 pathway (IFNGR2,
147569; BCL2L1, 600039; and JAK2, 147796) were upregulated. Patients
with STAT3 mutations presented more often with neutropenia and
rheumatoid arthritis than did patients without these mutations.

- Associations Pending Confirmation

For discussion of a possible association between variation in the STAT3
gene and Crohn disease, see IBD22 (612380).

For discussion of a possible association between variation in the STAT3
gene and susceptibility to multiple sclerosis, see MS (126200).

ANIMAL MODEL

Alternative splicing of the STAT3 gene produces 2 isoforms, STAT3-alpha
and a dominant-negative variant, STAT3-beta. In STAT3-beta, the 55
C-terminal residues of STAT3-alpha, spanning the intrinsic
transactivation domain, are replaced by 7 distinct residues. Yoo et al.
(2002) generated Stat3-beta-deficient mice by gene targeting. Despite
intact expression and phosphorylation of Stat3-alpha, overall Stat3
activity was impaired in Stat3-beta -/- cells. Global comparison of
transcription in Stat3-beta +/+ and Stat3-beta -/- cells revealed stable
differences. Stat3-beta-deficient mice exhibited diminished recovery
from endotoxic shock and hyperresponsiveness of a subset of
endotoxin-inducible genes in liver. The hepatic response to endotoxin in
wildtype mice was accompanied by a transient increase in the ratio of
Stat3-beta to Stat3-alpha. These findings indicated a critical role for
Stat3-beta in the control of systemic inflammation.

Welte et al. (2003) generated a strain of mice with tissue-specific
disruption of Stat3 in bone marrow cells during hematopoiesis. The
deletion caused death of the mice within 4 to 6 weeks after birth with
Crohn disease-like pathogenesis (see 266600) in both the small and large
intestine, including segmental inflammatory cell infiltration,
ulceration, bowel wall thickening, and granuloma formation. Deletion of
STAT3 causes significantly increased cell autonomous proliferation of
cells of myeloid lineage, both in vivo and in vitro. The authors
presented evidence that STAT3 may have an essential regulatory function
in the innate immune system. In particular, STAT3 may play a critical
role in the control of mucosal immune tolerance. A dramatic expansion of
myeloid lineages, causing massive infiltration of the intestine with
neutrophils, macrophages, and eosinophils, was thought to be caused by
pseudoactivated innate immune responses to bacterial lipopolysaccharide
as a result of the STAT3 deletion during hematopoiesis.

In cardiomyocyte-specific Stat3 knockout mice, Jacoby et al. (2003)
observed significantly more apoptosis after lipopolysaccharide treatment
than in wildtype mice, and Stat3 -/- cardiomyocytes secreted
significantly more TNFA (191160) in response to lipopolysaccharide than
wildtype. Mice with cardiomyocyte-specific Stat3 deficiency
spontaneously developed heart dysfunction with age, and histologic
examination of aged mice revealed a dramatic increase in cardiac
fibrosis compared to wildtype. Jacoby et al. (2003) concluded that STAT3
is crucial in cardiomyocyte resistance to inflammation and other acute
injury and in the pathogenesis of age-related heart failure.

Wang et al. (2004) showed that constitutive activation of Stat3
suppressed tumor expression of proinflammatory mediators in mice.
Introducing Stat3-beta, a dominant-negative variant, or Stat3 antisense
into mouse tumor cell lines increased expression of proinflammatory
cytokines and chemokines that activate innate immunity and dendritic
cells, leading to tumor-specific T-cell responses. Wang et al. (2004)
concluded that STAT3 signaling in tumors negatively regulates
inflammation, dendritic cell activity, and T-cell immunity. They
proposed that selective inhibition of STAT3 signaling would have not
only antitumor effects by suppressing growth and inducing apoptosis, but
would also activate innate and adaptive antitumor immunity.

Using gene targeting, Maritano et al. (2004) showed that in vivo
Stat3-beta is not a dominant-negative factor. In the absence of
Stat3-alpha, Stat3-beta rescued the embryonic lethality of the null
mutation and could induce expression of specific Stat3 target genes.
However, Stat3-alpha was essential for modulating cellular responses to
Il6 and mediating Il10 (124092) function in macrophages.

Inoue et al. (2004) showed that mice with liver-specific deficiency of
STAT3, generated using the Cre-loxP system, showed insulin resistance
associated with increased hepatic expression of gluconeogenic genes.
Restoration of hepatic STAT3 expression in these mice, using
adenovirus-mediated gene transfer, corrected the metabolic abnormalities
and the alterations in hepatic expression of gluconeogenic genes.
Overexpression of STAT3 in cultured hepatocytes inhibited gluconeogenic
gene expression independently of peroxisome proliferator-activated
receptor-gamma coactivator-1-alpha (PGC1A; 604517), an upstream
regulator of gluconeogenic genes. Liver-specific expression of a
constitutively active form of STAT3, achieved by infection with an
adenovirus vector, markedly reduced blood glucose, plasma insulin
concentrations, and hepatic gluconeogenic gene expression in diabetic
mice. Hepatic STAT3 signaling is thus essential for normal glucose
homeostasis and may provide new therapeutic targets for diabetes
mellitus (222100, 125853).

Hokuto et al. (2004) showed that cell-selective deletion of Stat3 in
mouse respiratory epithelial cells did not alter prenatal lung
morphogenesis or postnatal lung function. However, exposure of adult
Stat3-deleted mice to 95% oxygen caused a more rapidly progressive lung
injury associated with alveolar capillary leak and acute respiratory
distress, as well as increased epithelial cell injury and inflammatory
responses. Surfactant proteins and lipids were decreased or absent in
alveolar lavage material. Intratracheal treatment with exogenous
surfactant protein B (SFTPB; 178640) improved survival and lung
histology in Stat3-deleted mice during hyperoxia. Hokuto et al. (2004)
concluded that expression of STAT3 in respiratory epithelial cells is
not required for lung formation, but plays a critical role in
maintenance of surfactant homeostasis and lung function during oxygen
injury.

To assess the effect of Stat3 deficiency on mouse skin tumor
development, Chan et al. (2004) used the tumor initiator
7,12-dimethylbenz(alpha)anthracene (DMBA) and the tumor promoter
12-O-tetradecanoylphorbol-13-acetate (TPA) in the 2-stage chemical
carcinogenesis model. Stat3-deficient mice showed significantly reduced
epidermal proliferation following treatment with TPA because of a defect
in progression of the cell cycle from G1 to S phase; treatment with DMBA
resulted in a significant increase in the number of apoptotic
keratinocyte stem cells. Stat3-deficient mice were completely resistant
to skin tumor development when DMBA was used as the initiator and TPA as
the promoter. Abrogation of Stat3 function using a decoy oligonucleotide
inhibited the growth of initiated keratinocytes possessing an activated
Hras gene (190020), both in vitro and in vivo. Injection of Stat3 decoy
into skin tumors inhibited their growth. Chan et al. (2004) concluded
that STAT3 is required for de novo epithelial carcinogenesis through
maintaining the survival of DNA-damaged stem cells and through mediating
and maintaining the proliferation necessary for clonal expansion of
initiated cells during tumor promotion.

Gorogawa et al. (2004) disrupted Stat3 specifically in insulin (INS;
1767630)-producing cells in mice (Stat3-insKO mice). They observed
increased appetite and obesity at 8 weeks of age or later in Stat3-insKO
mice; the phenotype was not detectable before 6 weeks of age. The mutant
mice showed partial leptin resistance. Stat3-insKO mice tested at 5, 11,
and 24 weeks of age all showed impaired glucose tolerance, primarily due
to insufficient insulin secretion. Expression of mRNA for Glut2 (SLC2A2;
138160), Sur1 (ABCC8; 600509), and Vegfa (192240) was significantly
reduced in Stat3-insKO islets. Immunohistochemical analysis demonstrated
abnormal pancreatic islet morphology with altered distribution of alpha
cells. Gorogawa et al. (2004) concluded that STAT3 has a role in
maintaining glucose-mediated early-phase insulin secretion and normal
islet cell morphology.

Shen et al. (2005) had previously reported that 75% of C57BL/6 mice
lacking Stat3 ser727 phosphorylation showed early mortality and growth
retardation. They found that the long-term survivors showed no tissue
abnormalities but had increased susceptibility to doxorubicin-induced
heart failure. Introduction of this mutant allele into strain-129 mice
resulted in greater susceptibility to lipopolysaccharide-induced
toxicity. Shen et al. (2005) concluded that there is a continued need
for normal STAT3 transcriptional activity to resist different noxious
challenges mimicking conditions causing adult disease.

Using immunohistochemical analysis, Sano et al. (2005) demonstrated
activated STAT3 in epidermal keratinocytes from human psoriatic lesions
(see 177900). Transgenic mice with keratinocytes expressing a
constitutively active Stat3 developed skin lesions, either spontaneously
or in response to wounding, that closely resembled human psoriatic
plaques; in transgenic keratinocytes there was upregulation of several
molecules linked to the pathogenesis of psoriasis. The development of
psoriatic lesions in the transgenic mice required cooperation between
Stat3 activation in keratinocytes and activated T cells, and abrogation
of Stat3 function by a decoy oligonucleotide inhibited the onset and
reversed established psoriatic lesions.

Using a mouse model of spinal cord injury, Okada et al. (2006) showed
that Stat3 is a key regulator of reactive astrocytosis in the repair of
injured tissue during the subacute phase (initial 14 days after injury).
Selective disruption of the Stat3 gene in mice subjected to spinal cord
injury resulted in limited migration of reactive astrocytes, widespread
infiltration of inflammatory cells, and neural disruption and
demyelination compared to wildtype mice.

*FIELD* AV
.0001
HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANT
STAT3, VAL463DEL

In 3 presumably unrelated Japanese patients with hyper-IgE syndrome
(147060), Minegishi et al. (2007) identified heterozygosity for a 3-bp
deletion (1387delGTG) in the STAT3 gene, resulting in deletion of a
valine at position 463.

Holland et al. (2007) described the same mutation in a sporadic
Caucasian case of hyper-IgE syndrome.

.0002
HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANT
STAT3, ARG382TRP

In 2 presumably unrelated Japanese patients with hyper-IgE syndrome
(147060), Minegishi et al. (2007) identified heterozygosity for a
1144C-T transition in the STAT3 gene, resulting in an arg382-to-trp
(R382W) substitution.

In affected members of 7 families segregating hyper-IgE syndrome,
Holland et al. (2007) identified heterozygosity for the R382W mutation
in the STAT3 gene. Two of the families were black, 1 Hispanic, and the
remainder white.

In 1 of the original patients with 'Job syndrome' reported by Davis et
al. (1966), Renner et al. (2007) found the same heterozygous R382W
mutation. Her 2 sons and a grandson were also affected. Renner et al.
(2007) noted that arg382, which is highly conserved and directly
involved in DNA binding, accounted for nearly half of the STAT3
mutations identified by Minegishi et al. (2007) and Holland et al.
(2007). Also see 102582.0003.

.0003
HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANT
STAT3, ARG382GLN

In a Japanese patient with hyper-IgE syndrome (147060), Minegishi et al.
(2007) identified heterozygosity for a 1145G-A transition in the STAT3
gene, resulting in an arg382-to-gln (R382Q) substitution.

In affected members of 4 families segregating hyper-IgE syndrome,
Holland et al. (2007) identified heterozygosity for the R382Q mutation
in the STAT3 gene. One of the families was black and 3 were white.

.0004
HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANT
STAT3, ARG423GLN

In affected members of 2 families, 1 white and 1 Asian, segregating
hyper-IgE syndrome (147060), Holland et al. (2007) identified
heterozygosity for a 1268G-A transition in the STAT3 gene, resulting in
an arg423-to-gln (R423Q) substitution. A parent and daughter were
affected in the white family, and parent, son, and daughter in the Asian
family.

.0005
HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANT
STAT3, ARG383LEU

In a white-Hispanic patient with sporadic hyper-IgE syndrome (147060),
Holland et al. (2007) identified heterozygosity for a 1145G-T transition
in the STAT3 gene, resulting in an arg383-to-leu (R383L) substitution.

.0006
HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANT
STAT3, VAL637MET

In affected members of 6 families, all white, with hyper-IgE syndrome
(147060), Holland et al. (2007) identified heterozygosity for a 1909G-A
transition in the STAT3 gene, resulting in a val637-to-met (V637M)
substitution.

.0007
HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANT
STAT3, THR389ILE

Crosby et al. (2012) reported an African-American male with hyper-IgE
syndrome (HIES; 147060) who presented with dysphagia resistant to proton
pump inhibitors. He had a normal blood cell count and differential with
12% eosinophils and total IgE of 2728 kU/L. His HIES score was 53.
Genotype analysis revealed a mutation in exon 12 of the STAT3 gene that
resulted in a thr389-to-ile (T389I) substitution.

*FIELD* RF
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29. McLoughlin, R. M.; Jenkins, B. J.; Grail, D.; Williams, A. S.;
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30. Minegishi, Y.; Saito, M.; Tsuchiya, S.; Tsuge, I.; Takada, H.;
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32. Nakashima, K.; Yanagisawa, M.; Arakawa, H.; Kimura, N.; Hisatsune,
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33. Okada, S.; Nakamura, M.; Katoh, H.; Miyao, T.; Shimazaki, T.;
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34. Pfeffer, L. M.; Mullersman, J. E.; Pfeffer, S. R.; Murti, A.;
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35. Ram, P. T.; Horvath, C. M.; Iyengar, R.: Stat3-mediated transformation
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36. Renner, E. D.; Torgerson, T. R.; Rylaarsdam, S.; Anover-Sombke,
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37. Saeij, J. P. J.; Coller, S.; Boyle, J. P.; Jerome, M. E.; White,
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2007.

38. Sano, S.; Chan, K. S.; Carbajal, S.; Clifford, J.; Peavey, M.;
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39. Scoles, D. R.; Nguyen, V. D.; Qin, Y.; Sun, C.-X.; Morrison, H.;
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42. Siegel, A. M.; Heimall, J.; Freeman, A. F.; Hsu, A. P.; Brittain,
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43. Simon, A. R.; Vikis, H. G.; Stewart, S.; Fanburg, B. L.; Cochran,
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44. Vaisse, C.; Halaas, J. L.; Horvath, C. M.; Darnell, J. E., Jr.;
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45. Wang, T.; Niu, G.; Kortylewski, M.; Burdelya, L.; Shain, K.; Zhang,
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46. Wegrzyn, J.; Potla, R.; Chwae, Y.-J.; Sepuri, N. B. V.; Zhang,
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47. Welte, T.; Zhang, S. S. M.; Wang, T.; Zhang, Z.; Hesslein, D.
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48. Ying, Q.-L.; Wray, J.; Nichols, J.; Batlle-Morera, L.; Doble,
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49. Yoo, J.-Y.; Huso, D. L.; Nathans, D.; Desiderio, S.: Specific
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50. Yuan, Z.; Guan, Y.; Chatterjee, D.; Chin, Y. E.: Stat3 dimerization
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51. Zhang, Q.; Wang, H. Y.; Marzec, M.; Raghunath, P. N.; Nagasawa,
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52. Zhang, Y.; Cho, Y.-Y.; Petersen, B. L.; Bode, A. M.; Zhu, F.;
Dong, Z.: Ataxia telangiectasia mutated proteins, MAPKs, and RSK2
are involved in the phosphorylation of STAT3. J. Biol. Chem. 278:
12650-12659, 2003.

*FIELD* CN
Paul J. Converse - updated: 12/12/2013
Paul J. Converse - updated: 9/13/2013
Paul J. Converse - updated: 9/24/2012
Ada Hamosh - updated: 8/28/2012
Ada Hamosh - updated: 6/5/2012
Ada Hamosh - updated: 2/18/2010
Ada Hamosh - updated: 12/29/2009
Ada Hamosh - updated: 8/27/2009
Ada Hamosh - updated: 7/9/2009
Ada Hamosh - updated: 2/18/2009
Paul J. Converse - updated: 2/4/2009
Patricia A. Hartz - updated: 8/20/2008
Ada Hamosh - updated: 6/3/2008
Victor A. McKusick - updated: 10/22/2007
Paul J. Converse - updated: 1/30/2007
Cassandra L. Kniffin - updated: 8/2/2006
Marla J. F. O'Neill - updated: 2/2/2006
Ada Hamosh - updated: 11/14/2005
Paul J. Converse - updated: 9/14/2005
Marla J. F. O'Neill - updated: 3/17/2005
Marla J. F. O'Neill - updated: 3/4/2005
Ada Hamosh - updated: 1/27/2005
Marla J. F. O'Neill - updated: 11/22/2004
George E. Tiller - updated: 9/2/2004
Paul J. Converse - updated: 4/6/2004
Patricia A. Hartz - updated: 4/1/2004
Marla J. F. O'Neill - updated: 3/23/2004
Victor A. McKusick - updated: 1/22/2004
Paul J. Converse - updated: 1/21/2004
Victor A. McKusick - updated: 3/27/2003
Ada Hamosh - updated: 2/21/2003
Patricia A. Hartz - updated: 5/15/2002
Stylianos E. Antonarakis - updated: 3/25/2002
Ada Hamosh - updated: 10/20/2000
Ada Hamosh - updated: 12/30/1999
Stylianos E. Antonarakis - updated: 9/1/1999
Ada Hamosh - updated: 4/15/1999
Jennifer P. Macke - updated: 7/24/1997
Victor A. McKusick - updated: 6/20/1997
Mark H. Paalman - edited: 9/10/1996

*FIELD* CD
Victor A. McKusick: 7/13/1994

*FIELD* ED
mgross: 12/20/2013
mcolton: 12/12/2013
mgross: 9/13/2013
terry: 12/20/2012
mgross: 10/4/2012
terry: 9/24/2012
alopez: 8/29/2012
terry: 8/28/2012
alopez: 6/7/2012
terry: 6/5/2012
carol: 3/25/2010
ckniffin: 3/24/2010
alopez: 2/22/2010
terry: 2/18/2010
alopez: 1/4/2010
terry: 12/29/2009
wwang: 11/30/2009
alopez: 9/2/2009
terry: 8/27/2009
alopez: 7/16/2009
terry: 7/9/2009
alopez: 2/25/2009
terry: 2/18/2009
mgross: 2/4/2009
terry: 2/4/2009
terry: 1/7/2009
carol: 11/3/2008
carol: 10/29/2008
mgross: 8/20/2008
terry: 8/20/2008
alopez: 6/4/2008
terry: 6/3/2008
carol: 10/24/2007
carol: 10/23/2007
terry: 10/22/2007
ckniffin: 5/23/2007
mgross: 1/30/2007
carol: 8/9/2006
ckniffin: 8/2/2006
wwang: 2/3/2006
terry: 2/2/2006
alopez: 11/15/2005
terry: 11/14/2005
mgross: 9/14/2005
wwang: 3/17/2005
wwang: 3/16/2005
wwang: 3/10/2005
wwang: 3/9/2005
terry: 3/4/2005
wwang: 2/7/2005
wwang: 2/2/2005
terry: 1/27/2005
tkritzer: 11/23/2004
tkritzer: 11/22/2004
carol: 9/3/2004
terry: 9/2/2004
alopez: 5/3/2004
mgross: 4/16/2004
mgross: 4/6/2004
terry: 4/1/2004
carol: 3/26/2004
tkritzer: 3/23/2004
alopez: 2/17/2004
alopez: 1/23/2004
terry: 1/22/2004
mgross: 1/21/2004
cwells: 4/1/2003
terry: 3/27/2003
alopez: 2/25/2003
terry: 2/21/2003
carol: 5/15/2002
mgross: 3/25/2002
cwells: 6/8/2001
alopez: 10/20/2000
alopez: 12/30/1999
mgross: 9/1/1999
kayiaros: 7/12/1999
alopez: 4/15/1999
carol: 11/15/1998
jenny: 8/27/1997
terry: 6/23/1997
alopez: 6/20/1997
terry: 12/30/1996
terry: 12/11/1996
mark: 9/12/1996
mark: 9/11/1996
mark: 9/10/1996
jason: 7/13/1994

MIM 147060
*RECORD*
*FIELD* NO
147060
*FIELD* TI
#147060 HYPER-IgE RECURRENT INFECTION SYNDROME, AUTOSOMAL DOMINANT
;;HYPER-IgE SYNDROME, AUTOSOMAL DOMINANT;;
read moreHIES, AUTOSOMAL DOMINANT;;
JOB SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
hyper-IgE recurrent infection syndrome is caused by heterozygous
mutation in the STAT3 gene (102582) on chromosome 17q21.

See also autosomal recessive HIES (243700), which is caused by mutation
in the DOCK8 gene (611432), and tyrosine kinase-2 deficiency (611521),
which is caused by mutation in the TYK2 gene (176941) and has been
reported in a single patient.

DESCRIPTION

Hyper-IgE recurrent infection syndrome is a primary immunodeficiency
disorder characterized by chronic eczema, recurrent Staphylococcal
infections, increased serum IgE, and eosinophilia. Patients have a
distinctive coarse facial appearance, abnormal dentition,
hyperextensibility of the joints, and bone fractures (Buckley et al.,
1972; Grimbacher et al., 1999).

CLINICAL FEATURES

Davis et al. (1966) reported 2 unrelated girls with lifelong histories
of indolent Staphylococcal abscesses. Both had eczema soon after birth
and had persistent weeping lesions on the ears and face. The abscesses
were characterized as 'cold' because of the lack of surrounding warmth,
erythema, or tenderness. Both girls had red hair and were fair-skinned.
The authors suggested a defect in local resistance to Staphylococcal
infection. Further study of these girls by White et al. (1969) revealed
normal leukocyte functions. However, Hill et al. (1974) and Hill and
Quie (1974) found a defect in neutrophil granulocyte chemotaxis and very
high serum IgE levels in 4 girls with the disorder; 2 of the girls had
been reported by Davis et al. (1966).

Renner et al. (2007) provided a follow-up of 1 of the patients reported
by Davis et al. (1966). At 50 years of age, the woman had had lifelong
eczema, multiple atraumatic fractures, hyperkeratotic fingernails due to
candida infection, recurrent Staphylococcal abscesses, and pneumonia
with lung abscesses and pneumatocele formation. Two of her 3 sons and 1
grandson were also affected.

Buckley et al. (1972) described 2 male patients with features of Job
syndrome as originally described by Davis et al. (1966). Each boy had
extremely high serum IgE levels as well as immediate cutaneous
hypersensitivity reactions to Staphylococcus aureus and Candida
albicans. The authors also noted joint hyperextensibility and asymmetric
facies.

Van Scoy et al. (1975) described a 20-year-old woman and her daughter
who had recurrent bacterial infections and chronic mucocutaneous
candidiasis. Laboratory studies showed marked elevation of serum IgE,
defective neutrophil chemotaxis, and impaired lymphocyte response to
candida antigen. The mother's brother, father, and paternal grandfather
showed mild increases in IgE and mildly depressed chemotactic activity
of neutrophils.

Osteoporosis and a propensity to bone fracture, referred to by Brestel
et al. (1982) as 'osteogenesis imperfecta tarda,' was a recognized
feature of hyper-IgE syndrome. Kirchner et al. (1985) also noted the
association of hyper-IgE syndrome with osteoporosis and recurrent
fractures. Hoger et al. (1985) described the association with
craniosynostosis and discussed 3 reported cases.

Robinson et al. (1982) described a kindred brought to attention because
of a 6-year-old girl who showed features of both the hyper-IgE syndrome
and chronic granulomatous disease. Inheritance was possibly autosomal
dominant. Laboratory studies showed impaired T cell responses.

Donabedian and Gallin (1982) presented evidence suggesting that
mononuclear cells from patients with the hyper-IgE recurrent infection
syndrome produced an inhibitor of leukocyte chemotaxis.

Donabedian and Gallin (1983) provided a review of 13 patients with
hyper-IgE syndrome examined at the National Institutes of Health. Nine
of the 13 had coarse facies, with broad nasal bridge, prominent nose,
and irregularly proportioned cheeks and jaws. All had recurrent skin
infections, most by 3 months of age. All patients, except 1, had
recurrent pneumonias, and most had recurrent bronchitis and otitis. Many
patients developed pneumatoceles and most required chest tube drainage
and/or lobectomies. Seven of the 13 had Candidal infections of the
nails, vagina, or mouth. Three additional patients were described as
having a 'variant' of the disorder due to lack of cold abscesses and
serious sinopulmonary infection, declining serum IgE levels, and first
appearance of infection at age 17 years, respectively. Laboratory
studies showed mild to moderate eosinophilia. Impaired neutrophil
chemotaxis was not a constant feature, and it was not severe when it
occurred. There was some evidence for a chemotactic inhibitor.

In patients with hyper-IgE syndrome, Dreskin et al. (1985) demonstrated
deficiency of serum anti-Staph aureus IgA, salivary IgA, and salivary
anti-Staph aureus IgA. There was an inverse correlation between the
number of infections at mucosal surfaces and in adjacent lymph nodes and
the levels of these substances as well as of total serum IgE and total
serum IgD.

Lui and Inculet (1990) described a patient with presumed Job syndrome
and recurrent lung abscess necessitating lung resection. Serum IgE
levels were markedly elevated. Some of the lung abscesses appeared to be
due to Staph aureus; the resected right lower lobe showed an abscess
cavity with aspergilloma.

Borges et al. (1998) evaluated the facial features of 9 patients from 7
kindreds with Job syndrome. Consistent features included prominent
forehead with deep-set eyes, increased width of the nose, a full lower
lip, and thickening of the nose and ears. The mean alar width and outer
canthal distance were significantly increased. The authors concluded
that there is a recognizable face of Job syndrome.

The study of Grimbacher et al. (1999) established that the hyper-IgE
syndrome is a multisystem disorder. Grimbacher et al. (1999) studied 30
patients with hyper-IgE syndrome and 70 of their relatives. In addition
to the recurrent skin and pulmonary abscesses and extremely elevated
levels of IgE in serum, there are associated facial, dental, and
skeletal features. Nonimmunologic features of the hyper-IgE syndrome
were present in all patients older than 8 years. Failure or delay of
shedding of the primary teeth owing to lack of root resorption was
observed in 72%. Common findings among patients were recurrent fractures
(57%), hyperextensible joints (68%), and scoliosis (in 76% of patients
over 16 years of age). The classic triad of abscesses, pneumonia, and an
elevated IgE level was identified in 77% of all patients and in 85% of
those older than 8 years. In 6 (26%) of 23 adults, IgE levels declined
over time and came closer to or fell within the normal range.

Grimbacher et al. (1999) noted the unusual facial phenotype of the
hyper-IgE syndrome, which had been commented on by Davis et al. (1966)
and by Borges et al. (1998). By the age of 16 years, all of the patients
studied by Grimbacher et al. (1999) showed distinctive facial
characteristics, including facial asymmetry with a suggestion of
hemihypertrophy, prominent forehead, deep-set eyes, broad nasal bridge,
wide, fleshy nasal tip, and mild prognathism. The facial skin was rough,
with prominent pores. The interalar distance was increased. Head
circumference also tended to be larger than normal.

Crosby et al. (2012) reported a 35-year-old African-American male who
presented with dysphagia that was resistant to proton pump inhibitors.
The patient had a normal blood cell count and differential with 12%
eosinophils and total IgE of 2728 kU/L. Additional complaints included
constipation with soy and hives after eating fish. The patient had a
history of recurrent infections, including staphylococcal pneumonia, as
well as skin abscesses, fractures, and esophageal candidiasis. He had
undergone left lung pneumonectomy secondary to pneumatocele formation
after severe pneumonia. The patient had coarse facies, wide nasal
bridge, moderate eczema, and hyperextensibility, and his HIES score was
53. He was found to have a ringed esophagus. Histopathologic analysis of
the middle third of the esophagus revealed elevated eosinophil numbers.

PATHOGENESIS

Milner et al. (2008) showed that interleukin-17 (IL17; see 603149)
production by T cells is absent in individuals with hyper-IgE syndrome
(HIES). They observed that ex vivo T cells from subjects with HIES
failed to produce IL17, but not IL2 (147680), TNF (191160), or IFNG
(147570), on mitogenic stimulation with staphylococcal enterotoxin B or
on antigenic stimulation with Candida albicans or streptokinase.
Purified naive T cells were unable to differentiate into IL17-producing
(TH17) T helper cells in vitro and had lower expression of
retinoid-related orphan receptor (ROR)-gamma-t (602943), which is
consistent with a crucial role for STAT3 (102582) signaling in the
generation of TH17 cells. TH17 cells are an important subset of helper T
cells that are believed to be critical in the clearance of fungal and
extracellular bacterial infections. Thus, Milner et al. (2008) concluded
that the inability to produce TH17 cells is a mechanism underlying the
susceptibility to recurrent infections commonly seen in HIES.

Independently, Ma et al. (2008) and de Beaucoudrey et al. (2008)
presented findings similar to those of Milner et al. (2008).

Using flow cytometric analysis, Siegel et al. (2011) demonstrated a
significant reduction in central memory (i.e., expressing CD27, 186711,
and CD45RO, 151460) CD4 (186940)-positive and CD8 (see 186910)-positive
T cells in autosomal dominant HIES patients that was not due to
apoptosis or cell turnover. Stimulation of naive T cells in the presence
of IL7 (146660) or IL15 (600554) failed to restore memory cell
generation in HIES patients. Impaired differentiation was associated
with decreased expression of 2 STAT3-responsive transcription factors,
BCL6 (109565) and SOCS3 (604176). Siegel et al. (2011) found that HIES
patients had increased risk for reactivation of varicella zoster that
was associated with poor CD4-positive T-cell responses. HIES patients
also had greater detectable Epstein-Barr virus (EBV) viremia that was
associated with compromised T-cell memory to EBV. Siegel et al. (2011)
concluded that STAT3 has a specific role in central memory T-cell
formation.

INHERITANCE

Blum et al. (1977) reported hyper-IgE syndrome with recurrent severe
Staphylococcal infections, eczematoid rash, and eosinophilia in 2
successive generations of a family.

Buckley and Becker (1978) reviewed 20 patients with HIE syndrome. Since
both males and females were affected in successive generations, they
suggested autosomal dominant inheritance with incomplete penetrance.

Leung and Geha (1988) reported 9 patients with the disorder. None of the
patients had a family history of recurrent infections or consanguinity,
indicating de novo or sporadic occurrence.

Grimbacher et al. (1999) concluded that the hyper-IgE syndrome is
inherited as an autosomal dominant disorder with variable expressivity.
They presented pedigrees of 6 families, 4 of which had definitely
affected cases in 2 successive generations. One family had affected
father and son. Of 27 relatives at risk for inheriting the disorder, 10
were fully affected, 11 were unaffected, and 6 had combinations of mild
immunologic, dental, and skeletal features of the hyper-IgE syndrome.

DIAGNOSIS

Leung and Geha (1988) reviewed cases of HIE syndrome and concluded that
the most distinctive feature of the disorder is elevated serum IgE
levels. They also emphasized the necessity to distinguish the HIE
syndrome from atopic dermatitis (see, e.g., 603165), a disorder with
which it is frequently confused.

- Distinction from Atopic Dermatitis

Grimbacher et al. (1999) noted several distinguishing features of HIE
syndrome and severe atopic dermatitis. In HIE syndrome, Staphylococcus
aureus infections are deep seeded and serious, non-Staph aureus
infections are frequent, respiratory allergy is rare, and onset occurs
between 1 and 8 weeks. In atopic dermatitis, Staphylococcus aureus
infections are superficial and involve only the skin, non-Staph aureus
infections are rare, respiratory allergy is common, and onset occurs
after age 2 months. Patients with HIE often have coarse facies, which is
not present in patients with atopic dermatitis. Severe atopic dermatitis
is at least 10 times more common than HIE.

CLINICAL MANAGEMENT

In a prospective trial of levamisole in a large group of patients with
Job syndrome, Donabedian et al. (1982) found no decrease in the
propensity to infection, despite the fact that the drug clearly reversed
the chemotactic defect. In a response to this report, Swim et al. (1982)
suggested that the leukocyte defect and the proneness to infection in
Job syndrome may be unrelated.

MAPPING

The finding of mutations in the STAT3 gene in patients with HIES (see
MOLECULAR GENETICS) established that one form of the disorder maps to
chromosome 17q21.

- Genetic Heterogeneity

Grimbacher et al. (1999) scored 19 kindreds with multiple cases of HIES
for clinical and laboratory findings and genotyped the members of these
19 kindreds with polymorphic markers in a candidate region on chromosome
4. This region was selected because 1 patient with sporadic HIES plus
autism and mental retardation was found to have a supernumerary marker
chromosome, derived from a 15- to 20-cM interstitial deletion in 4q21.
Linkage analysis in the 19 kindreds showed a maximum 2-point lod score
of 3.61 at a recombination fraction of 0.0 with marker D4S428.
Multipoint analysis and simulation testing confirmed that the proximal
4q region contains a disease locus for HIES. Six kindreds did not show
linkage to 4q, indicating genetic heterogeneity.

MOLECULAR GENETICS

Minegishi et al. (2007) found that 8 of 15 unrelated nonfamilial HIES
patients had heterozygous mutations in the STAT3 gene (see, e.g.,
102582.0001-102582.0003). None of the parents or sibs of the patients
had the mutant STAT3 allele, suggesting that these were de novo
mutations. All 5 identified mutations were located in the DNA-binding
domain of STAT3. The peripheral blood cells showed defective responses
to cytokines, including interleukin-6 (IL6; 147620) and interleukin-10
(IL10; 124092), and the DNA-binding ability of STAT3 in these cells was
greatly diminished. All 5 mutants were nonfunctional by themselves and
showed dominant-negative effects when coexpressed with wildtype STAT3.

Holland et al. (2007) collected longitudinal clinical data on patients
with the hyper-IgE syndrome and their families and assayed the levels of
cytokine secreted by stimulated leukocytes and the gene expression in
resting and stimulated cells. These data implicated STAT3 as a candidate
gene, which they then sequenced. They identified missense mutations and
single-codon in-frame deletions in STAT3 in 50 familial and sporadic
cases of the hyper-IgE syndrome. Eighteen discrete mutations, 5 of which
were hotspots, were predicted to affect directly the DNA-binding and SRC
homology-2 (SH2) domains (see, e.g., 102582.0001-102582.0006).

Renner et al. (2007) demonstrated that one of the original patients with
Job syndrome described by Davis et al. (1966) had a heterozygous
arg382-to-trp mutation (R382W; 102582.0002) in the STAT3 gene.

In the patient they reported with food allergies, a high score for HIES,
and eosinophilic esophagitis, Crosby et al. (2012) identified a
thr389-to-ile (T389I; 102582.0007) mutation in the STAT3 gene.

NOMENCLATURE

Davis et al. (1966) called the disorder 'Job syndrome' because of
phenotypic similarity to the biblical figure Job: 'Satan...smote Job
with sore boils from the sole of his foot unto his crown' (Job 2:7).

HISTORY

The first description of hyper-IgE syndrome (Davis et al., 1966) in
girls with fair skin and red hair suggested an association with
pigmentation. Later studies showed that the disorder is not associated
with red hair or fair skin and that it occurs in both males and females
(Donabedian and Gallin, 1983).

Bannatyne et al. (1969) described 2 affected sisters whose parents were
second cousins. Despite the fact that their parents were dark-skinned
and dark-haired southern Italian immigrants, the proband had red hair,
fair skin, and reddish-brown eyes. A sister was clinically well, but had
red hair and a mild leukocyte defect demonstrated in vitro. Donabedian
and Gallin (1983) concluded that the patients reported by Bannatyne et
al. (1969) likely did not have HIES because neutrophils from those
patients were unable to kill Staphylococci. Neutrophils isolated from
patients with HIES do not show an inability to kill Staph bacteria.

Witemeyer and Van Epps (1976) reported a brother and sister with
defective cellular chemotaxis, recurrent infection, and red hair.
However, neutrophil random mobility and bactericidal activity were
normal, suggesting a different disorder.

*FIELD* SA
Buckley and Sampson (1981); Geha et al. (1981); Leung et al. (1986)
*FIELD* RF
1. Bannatyne, R. M.; Skowron, P. N.; Weber, J. L.: Job's syndrome,
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1969.

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3. Borges, W. G.; Hensley, T.; Carey, J. C.; Petrak, B. A.; Hill,
H. R.: The face of Job. J. Pediat. 133: 303-305, 1998.

4. Brestel, E. P.; Klingberg, W. G.; Veltri, R. W.; Dorn, J. S.:
Osteogenesis imperfecta tarda in a child with hyper IgE syndrome. Am.
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5. Buckley, R. H.; Becker, W. G.: Abnormalities in the regulation
of human IgE synthesis. Immun. Rev. 41: 288-314, 1978.

6. Buckley, R. H.; Sampson, H. A.: The hyperimmunoglobulinemia E
syndrome.In: Franklin, E. C.: Clinical Immunology Update. New York:
Elsevier/North Holland Biomedical Press (pub.) 1981. Pp. 148-167.

7. Buckley, R. H.; Wray, B. B.; Belmaker, E. Z.: Extreme hyperimmunoglobulin
E and undue susceptibility to infection. Pediatrics 49: 59-70, 1972.

8. Crosby, K.; Swender, D.; Chernin, L.; Hafez-Khayyata, S.; Ochs,
H.; Tcheurekdjian, H.; Hostoffer, R.: Signal transducer and activator
of transcription 3 mutation with invasive eosinophilic disease. Allergy
Rhinol. 3: e94-e97, 2012.

9. Davis, S. D.; Schaller, J.; Wedgwood, R. J.: Job's syndrome: recurrent,
'cold,' staphylococcal abscesses. Lancet 287: 1013-1015, 1966. Note:
Originally Volume I.

10. de Beaucoudrey, L.; Puel, A.; Filipe-Santos, O.; Cobat, A.; Ghandil,
P.; Chrabieh, M.; Feinberg, J.; von Bernuth, H.; Samarina, A.; Janniere,
L.; Fieschi, C.; Stephan, J.-L.; Boileau, C.; and 33 others: Mutations
in STAT3 and IL12RB1 impair the development of human IL-17-producing
T cells. J. Exp. Med. 205: 1543-1550, 2008.

11. Donabedian, H.; Alling, D. W.; Gallin, J. I.: Levamisole is inferior
to placebo in the hyperimmunoglobulin E recurrent-infection (Job's)
syndrome. New Eng. J. Med. 307: 290-292, 1982.

12. Donabedian, H.; Gallin, J. I.: The hyperimmunoglobulin E recurrent-infection
(Job's) syndrome: a review of the NIH experience and the literature. Medicine 62:
195-208, 1983.

13. Donabedian, H.; Gallin, J. I.: Mononuclear cells from patients
with the hyperimmunoglobulin E-recurrent-infection syndrome produce
an inhibitor of leukocyte chemotaxis. J. Clin. Invest. 69: 1155-1163,
1982.

14. Dreskin, S. C.; Goldsmith, P. K.; Gallin, J. I.: Immunoglobulins
in the hyperimmunoglobulin E and recurrent infection (Job's) syndrome:
deficiency of anti-Staphylococcus aureus immunoglobulin A. J. Clin.
Invest. 75: 26-34, 1985.

15. Geha, R. S.; Reinherz, E.; Leung, D.; McKee, K. T., Jr.; Schlossman,
S.; Rosen, F. S.: Deficiency of suppressor T cells in the hyperimmunoglobulin
E syndrome. J. Clin. Invest. 68: 783-791, 1981.

16. Grimbacher, B.; Holland, S. M.; Gallin, J. I.; Greenberg, F.;
Hill, S. C.; Malech, H. L.; Miller, J. A.; O'Connell, A. C.; Puck,
J. M.: Hyper-IgE syndrome with recurrent infections--an autosomal
dominant multisystem disorder. New Eng. J. Med. 340: 692-702, 1999.

17. Grimbacher, B.; Schaffer, A. A.; Holland, S. M.; Davis, J.; Gallin,
J. I.; Malech, H. L.; Atkinson, T. P.; Belohradsky, B. H.; Buckley,
R. H.; Cossu, F.; Espanol, T.; Garty, B.-Z.; Matamoros, N.; Myers,
L. A.; Nelson, R. P.; Ochs, H. D.; Renner, E. D.; Wellinghausen, N.;
Puck, J. M.: Genetic linkage of hyper-IgE syndrome to chromosome
4. Am. J. Hum. Genet. 65: 735-744, 1999.

18. Hill, H. R.; Ochs, H. D.; Quie, P. G.; Clark, R. A.; Pabst, H.
F.; Klebanoff, S. J.; Wedgwood, R. J.: Defect in neutrophil granulocyte
chemotaxis in Job's syndrome of recurrent 'cold' staphylococcal abscesses. Lancet 304:
617-619, 1974. Note: Originally Volume 2.

19. Hill, H. R.; Quie, P. G.: Raised serum-IgE levels and defective
neutrophil chemotaxis in three children with eczema and recurrent
bacterial infections. Lancet 303: 183-187, 1974. Note: Originally
Volume 1.

20. Hoger, P. H.; Boltshauser, E.; Hitzig, W. H.: Craniosynostosis
in hyper-IgE-syndrome. Europ. J. Pediat. 144: 414-417, 1985.

21. Holland, S. M.; DeLeo, F. R.; Elloumi, H. Z.; Hsu, A. P.; Uzel,
G.; Brodsky, N.; Freeman, A. F.; Demidowich, A.; Davis, J.; Turner,
M. L.; Anderson, V. L.; Darnell, D. N.; and 13 others: STAT3 mutations
in the hyper-IgE syndrome. New Eng. J. Med. 357: 1608-1619, 2007.

22. Kirchner, S. G.; Sivit, C. J.; Wright, P. F.: Hyperimmunoglobulinemia
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23. Leung, D. Y. M.; Frankel, R.; Wood, N.; Geha, R. S.: Potentiation
of human immunoglobulin E synthesis by plasma immunoglobulin E binding
factors from patients with the hyperimmunoglobulin E syndrome. J.
Clin. Invest. 77: 952-957, 1986.

24. Leung, D. Y. M.; Geha, R. S.: Clinical and immunologic aspects
of the hyperimmunoglobulin E syndrome. Hemat. Oncol. Clin. North
Am. 2: 81-100, 1988.

25. Lui, R. C.; Inculet, R. I.: Job's syndrome: a rare cause of recurrent
lung abscess in childhood. Ann. Thorac. Surg. 50: 992-994, 1990.

26. Ma, C. S.; Chew, G. Y. J.; Simpson, N.; Priyadarshi, A.; Wong,
M.; Grimbacher, B.; Fulcher, D. A.; Tangye, S. G.; Cook, M. C.: Deficiency
of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J.
Exp. Med. 205: 1551-1557, 2008.

27. Milner, J. D.; Brenchley, J. M.; Laurence, A.; Freeman, A. F.;
Hill, B. J.; Elias, K. M.; Kanno, Y.; Spalding, C.; Elloumi, H. Z.;
Paulson, M. L.; Davis, J.; Hsu, A.; Asher, A. I.; O'Shea, J.; Holland,
S. M.; Paul, W. E.; Douek, D. C.: Impaired TH17 cell differentiation
in subjects with autosomal dominant hyper-IgE syndrome. Nature 452:
773-776, 2008.

28. Minegishi, Y.; Saito, M.; Tsuchiya, S.; Tsuge, I.; Takada, H.;
Hara, T.; Kawamura, N.; Ariga, T.; Pasic, S.; Stojkovic, O.; Metin,
A.; Karasuyama, H.: Dominant-negative mutations in the DNA-binding
domain of STAT3 cause hyper-IgE syndrome. Nature 448: 1058-1062,
2007.

29. Renner, E. D.; Torgerson, T. R.; Rylaarsdam, S.; Anover-Sombke,
S.; Golob, K.; LaFlam, T.; Zhu, Q.; Ochs, H. D.: STAT3 mutation in
the original patient with Job's syndrome. (Letter) New Eng. J. Med. 357:
1667-1668, 2007.

30. Robinson, M. F.; McGregor, R.; Collins, R.; Cheung, K.: Combined
neutrophil and T-cell deficiency: initial report of a kindred with
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31. Siegel, A. M.; Heimall, J.; Freeman, A. F.; Hsu, A. P.; Brittain,
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1969. Note: Originally Volume 1.

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Pediat. 89: 33-37, 1976.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Face];
Coarse facies;
Asymmetric face;
Prominent forehead;
Mild prognathism;
[Eyes];
Hypertelorism;
[Nose];
Broad nose;
Thickening of the soft tissue of the nose;
[Mouth];
High-arched palate;
[Teeth];
Retained primary teeth;
Reduced resorption of primary tooth roots

RESPIRATORY:
Recurrent sinopulmonary infections;
[Lung];
Pneumatocele formation

SKELETAL:
Joint hyperextensibility;
Decreased bone mineral density;
Recurrent fractures;
[Skull];
Craniosynostosis (rare);
[Spine];
Scoliosis;
Vertebral body abnormalities

SKIN, NAILS, HAIR:
[Skin];
Eczema, severe;
Recurrent skin abscesses

IMMUNOLOGY:
Recurrent Staphylococcus aureus infections;
Abscesses are 'cold,' lacking erythema, heat, and swelling;
Recurrent fungal infections

LABORATORY ABNORMALITIES:
Increased serum IgE;
Eosinophilia

MISCELLANEOUS:
Onset in infancy

MOLECULAR BASIS:
Caused by mutation in the signal transducer and activator of transcription-3
gene (STAT3, 102582.0001)

*FIELD* CN
Cassandra L. Kniffin - revised: 10/9/2007

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 05/18/2011
joanna: 12/5/2008
joanna: 3/18/2008
ckniffin: 10/9/2007

*FIELD* CN
Paul J. Converse - updated: 12/20/2013
Paul J. Converse - updated: 9/13/2013
Paul J. Converse - updated: 9/24/2012
Ada Hamosh - updated: 5/21/2008
Victor A. McKusick - updated: 10/22/2007
Cassandra L. Kniffin - reorganized: 10/9/2007
Cassandra L. Kniffin - updated: 10/9/2007
Victor A. McKusick - updated: 9/20/1999
Victor A. McKusick - updated: 3/5/1999

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
mgross: 12/20/2013
mcolton: 12/12/2013
carol: 11/6/2013
mgross: 9/13/2013
carol: 8/6/2013
mgross: 10/4/2012
terry: 9/24/2012
alopez: 1/7/2010
wwang: 11/30/2009
terry: 4/29/2009
terry: 4/8/2009
terry: 2/3/2009
alopez: 5/28/2008
terry: 5/21/2008
carol: 3/19/2008
ckniffin: 10/26/2007
carol: 10/24/2007
carol: 10/23/2007
terry: 10/22/2007
carol: 10/9/2007
ckniffin: 10/9/2007
mgross: 3/17/2004
carol: 3/14/2000
terry: 3/14/2000
jlewis: 9/29/1999
terry: 9/20/1999
carol: 3/5/1999
terry: 3/5/1999
mimadm: 11/5/1994
carol: 5/16/1994
terry: 1/26/1994
carol: 4/27/1992
supermim: 3/16/1992
supermim: 3/20/1990