RBCC Red Blood Cell Collection

STAT5B [Confidence: low (only semi-automatic identification from reviews)]
Signal transducer and activator of transcription 5B
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P51692
ID STA5B_HUMAN Reviewed; 787 AA.
AC P51692; Q8WWS8;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 16-JAN-2004, sequence version 2.
DT 22-JAN-2014, entry version 143.
DE RecName: Full=Signal transducer and activator of transcription 5B;
GN Name=STAT5B;
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].
RX PubMed=8732682; DOI=10.1210/me.10.5.508;
RA Silva C.M., Lu H., Day R.N.;
RT "Characterization and cloning of STAT5 from IM-9 cells and its
RT activation by growth hormone.";
RL Mol. Endocrinol. 10:508-518(1996).
RN [2]
RP SEQUENCE REVISION TO 628; 717 AND 720.
RA Silva C.M., Lu H.;
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=8631883; DOI=10.1074/jbc.271.18.10690;
RA Lin J.-X., Mietz J., Modi W.S., John S., Leonard W.J.;
RT "Cloning of human Stat5B. Reconstitution of interleukin-2-induced
RT Stat5A and Stat5B DNA binding activity in COS-7 cells.";
RL J. Biol. Chem. 271:10738-10744(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=12039059; DOI=10.1016/S0378-1119(02)00421-3;
RA Ambrosio R., Fimiani G., Monfregola J., Sanzari E., De Felice N.,
RA Salerno M.C., Pignata C., D'Urso M., Ursini M.V.;
RT "The structure of human STAT5A and B genes reveals two regions of
RT nearly identical sequence and an alternative tissue specific STAT5B
RT promoter.";
RL Gene 285:311-318(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph;
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 PHOSPHORYLATION BY INSR, INTERACTION WITH INSR, AND MUTAGENESIS OF
RP THR-684.
RX PubMed=9428692; DOI=10.1111/j.1432-1033.1997.0411a.x;
RA Sawka-Verhelle D., Filloux C., Tartare-Deckert S., Mothe I.,
RA Van Obberghen E.;
RT "Identification of Stat 5B as a substrate of the insulin receptor.";
RL Eur. J. Biochem. 250:411-417(1997).
RN [7]
RP INTERACTION WITH NMI.
RX PubMed=9989503; DOI=10.1016/S0092-8674(00)80965-4;
RA Zhu M.-H., John S., Berg M., Leonard W.J.;
RT "Functional association of Nmi with Stat5 and Stat1 in IL-2- and
RT IFNgamma-mediated signaling.";
RL Cell 96:121-130(1999).
RN [8]
RP PHOSPHORYLATION AT TYR-699, AND MUTAGENESIS OF TYR-699.
RX PubMed=12411494; DOI=10.1093/emboj/cdf562;
RA Klejman A., Schreiner S.J., Nieborowska-Skorska M., Slupianek A.,
RA Wilson M., Smithgall T.E., Skorski T.;
RT "The Src family kinase Hck couples BCR/ABL to STAT5 activation in
RT myeloid leukemia cells.";
RL EMBO J. 21:5766-5774(2002).
RN [9]
RP FUNCTION IN PROLACTIN SIGNALING PATHWAY, PHOSPHORYLATION, AND
RP DEPHOSPHORYLATION BY PTPN2.
RX PubMed=11773439; DOI=10.1210/me.16.1.58;
RA Aoki N., Matsuda T.;
RT "A nuclear protein tyrosine phosphatase TC-PTP is a potential negative
RT regulator of the PRL-mediated signaling pathway: dephosphorylation and
RT deactivation of signal transducer and activator of transcription 5a
RT and 5b by TC-PTP in nucleus.";
RL Mol. Endocrinol. 16:58-69(2002).
RN [10]
RP INTERACTION WITH NCOA1.
RX PubMed=12954634; DOI=10.1074/jbc.M303644200;
RA Litterst C.M., Kliem S., Marilley D., Pfitzner E.;
RT "NCoA-1/SRC-1 is an essential coactivator of STAT5 that binds to the
RT FDL motif in the alpha-helical region of the STAT5 transactivation
RT domain.";
RL J. Biol. Chem. 278:45340-45351(2003).
RN [11]
RP PHOSPHORYLATION IN RESPONSE TO FLT3 SIGNALING.
RX PubMed=14504097; DOI=10.1182/blood-2003-02-0418;
RA Taketani T., Taki T., Sugita K., Furuichi Y., Ishii E., Hanada R.,
RA Tsuchida M., Sugita K., Ida K., Hayashi Y.;
RT "FLT3 mutations in the activation loop of tyrosine kinase domain are
RT frequently found in infant ALL with MLL rearrangements and pediatric
RT ALL with hyperdiploidy.";
RL Blood 103:1085-1088(2004).
RN [12]
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 [13]
RP PHOSPHORYLATION BY JAK2.
RX PubMed=15121872; DOI=10.1128/MCB.24.10.4557-4570.2004;
RA Kurzer J.H., Argetsinger L.S., Zhou Y.J., Kouadio J.L., O'Shea J.J.,
RA Carter-Su C.;
RT "Tyrosine 813 is a site of JAK2 autophosphorylation critical for
RT activation of JAK2 by SH2-B beta.";
RL Mol. Cell. Biol. 24:4557-4570(2004).
RN [14]
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 [15]
RP INVOLVEMENT IN GHII.
RX PubMed=15827093; DOI=10.1210/jc.2005-0515;
RA Hwa V., Little B., Adiyaman P., Kofoed E.M., Pratt K.L., Ocal G.,
RA Berberoglu M., Rosenfeld R.G.;
RT "Severe growth hormone insensitivity resulting from total absence of
RT signal transducer and activator of transcription 5b.";
RL J. Clin. Endocrinol. Metab. 90:4260-4266(2005).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-193, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [17]
RP PHOSPHORYLATION AT TYR-699 BY PTK6.
RX PubMed=17997837; DOI=10.1186/bcr1794;
RA Weaver A.M., Silva C.M.;
RT "Signal transducer and activator of transcription 5b: a new target of
RT breast tumor kinase/protein tyrosine kinase 6.";
RL Breast Cancer Res. 9:R79-R79(2007).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-193, 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 [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-128, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-193, 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 [22]
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 [23]
RP PHOSPHORYLATION IN RESPONSE TO KIT SIGNALING.
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 [24]
RP VARIANT GHII PRO-630.
RX PubMed=13679528; DOI=10.1056/NEJMoa022926;
RA Kofoed E.M., Hwa V., Little B., Woods K.A., Buckway C.K., Tsubaki J.,
RA Pratt K.L., Bezrodnik L., Jasper H., Tepper A., Heinrich J.J.,
RA Rosenfeld R.G.;
RT "Growth hormone insensitivity associated with a STAT5b mutation.";
RL N. Engl. J. Med. 349:1139-1147(2003).
RN [25]
RP VARIANT GHII SER-646, AND CHARACTERIZATION OF VARIANT GHII SER-646.
RX PubMed=22419735; DOI=10.1210/jc.2011-2554;
RA Scaglia P.A., Martinez A.S., Feigerlova E., Bezrodnik L.,
RA Gaillard M.I., Di Giovanni D., Ballerini M.G., Jasper H.G.,
RA Heinrich J.J., Fang P., Domene H.M., Rosenfeld R.G., Hwa V.;
RT "A Novel Missense Mutation in the SH2 Domain of the STAT5B Gene
RT Results in a transcriptionally inactive STAT5b associated with severe
RT IGF-I deficiency, immune dysfunction, and lack of pulmonary disease.";
RL J. Clin. Endocrinol. Metab. 97:E830-839(2012).
CC -!- FUNCTION: Carries out a dual function: signal transduction and
CC activation of transcription. Mediates cellular responses to the
CC cytokine KITLG/SCF and other growth factors. Binds to the GAS
CC element and activates PRL-induced transcription.
CC -!- SUBUNIT: Forms a homodimer or a heterodimer with a related family
CC member. Binds NR3C1 (By similarity). Interacts with NCOA1, NMI and
CC SOCS7. Interacts (via SH2 domain) with INSR.
CC -!- INTERACTION:
CC Q96EY1:DNAJA3; NbExp=2; IntAct=EBI-1186119, EBI-356767;
CC Q13287:NMI; NbExp=7; IntAct=EBI-1186119, EBI-372942;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity). Nucleus (By
CC similarity). Note=Translocated into the nucleus in response to
CC phosphorylation (By similarity).
CC -!- PTM: Tyrosine phosphorylated in response to signaling via
CC activated KIT, resulting in translocation to the nucleus. Tyrosine
CC phosphorylated in response to signaling via activated FLT3; wild-
CC type FLT3 results in much weaker phosphorylation than
CC constitutively activated mutant FLT3. Alternatively, can be
CC phosphorylated by JAK2. Phosphoryation at Tyr-699 by PTK6 or HCK
CC leads to an increase of its transcriptional activity.
CC Dephosphorylation on tyrosine residues by PTPN2 negatively
CC regulates prolactin signaling pathway.
CC -!- DISEASE: Growth hormone insensitivity with immunodeficiency (GHII)
CC [MIM:245590]: A disease characterized by short stature, growth
CC hormone deficiency in the presence of normal to elevated
CC circulating concentrations of growth hormone, resistance to
CC hexogeneous growth hormone therapy, and recurrent infections.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the transcription factor STAT family.
CC -!- SIMILARITY: Contains 1 SH2 domain.
CC -!- WEB RESOURCE: Name=STAT5Bbase; Note=STAT5B mutation db;
CC URL="http://bioinf.uta.fi/STAT5Bbase/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=STAT5 entry;
CC URL="http://en.wikipedia.org/wiki/STAT5";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/STAT5BID217ch17q21.html";
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DR EMBL; U48730; AAC50485.2; -; mRNA.
DR EMBL; U47686; AAC50491.1; -; mRNA.
DR EMBL; AJ412888; CAD19638.1; -; Genomic_DNA.
DR EMBL; AJ412889; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; AJ412890; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; AJ412891; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; AJ412892; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; AJ412893; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; AJ412894; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; AJ412895; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; AJ412896; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; AJ412897; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; AJ412898; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; AJ412899; CAD19638.1; JOINED; Genomic_DNA.
DR EMBL; BC065227; AAH65227.1; -; mRNA.
DR RefSeq; NP_036580.2; NM_012448.3.
DR UniGene; Hs.595276; -.
DR ProteinModelPortal; P51692; -.
DR SMR; P51692; 4-686.
DR IntAct; P51692; 13.
DR MINT; MINT-132900; -.
DR STRING; 9606.ENSP00000293328; -.
DR BindingDB; P51692; -.
DR ChEMBL; CHEMBL5817; -.
DR DrugBank; DB01254; Dasatinib.
DR PhosphoSite; P51692; -.
DR DMDM; 41019536; -.
DR PaxDb; P51692; -.
DR PeptideAtlas; P51692; -.
DR PRIDE; P51692; -.
DR DNASU; 6777; -.
DR Ensembl; ENST00000293328; ENSP00000293328; ENSG00000173757.
DR GeneID; 6777; -.
DR KEGG; hsa:6777; -.
DR UCSC; uc002hzh.3; human.
DR CTD; 6777; -.
DR GeneCards; GC17M040351; -.
DR HGNC; HGNC:11367; STAT5B.
DR HPA; CAB004298; -.
DR MIM; 245590; phenotype.
DR MIM; 604260; gene.
DR neXtProt; NX_P51692; -.
DR Orphanet; 220465; Laron syndrome with immunodeficiency.
DR PharmGKB; PA36186; -.
DR eggNOG; NOG245085; -.
DR HOVERGEN; HBG107486; -.
DR InParanoid; P51692; -.
DR KO; K11224; -.
DR OMA; VREATNS; -.
DR OrthoDB; EOG73JKTT; -.
DR PhylomeDB; P51692; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P51692; -.
DR ChiTaRS; STAT5B; human.
DR GeneWiki; STAT5B; -.
DR GenomeRNAi; 6777; -.
DR NextBio; 26454; -.
DR PMAP-CutDB; P51692; -.
DR PRO; PR:P51692; -.
DR ArrayExpress; P51692; -.
DR Bgee; P51692; -.
DR CleanEx; HS_STAT5B; -.
DR Genevestigator; P51692; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0003682; F:chromatin binding; ISS:UniProtKB.
DR GO; GO:0003690; F:double-stranded DNA binding; IEA:Ensembl.
DR GO; GO:0046983; F:protein dimerization activity; ISS:UniProtKB.
DR GO; GO:0000979; F:RNA polymerase II core promoter sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0003700; F:sequence-specific DNA binding transcription factor activity; TAS:ProtInc.
DR GO; GO:0004871; F:signal transducer activity; IEA:Ensembl.
DR GO; GO:0006103; P:2-oxoglutarate metabolic process; ISS:BHF-UCL.
DR GO; GO:0006953; P:acute-phase response; IEA:Ensembl.
DR GO; GO:0000255; P:allantoin metabolic process; ISS:BHF-UCL.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; ISS:UniProtKB.
DR GO; GO:0006101; P:citrate metabolic process; ISS:BHF-UCL.
DR GO; GO:0006600; P:creatine metabolic process; ISS:BHF-UCL.
DR GO; GO:0046449; P:creatinine metabolic process; ISS:BHF-UCL.
DR GO; GO:0046543; P:development of secondary female sexual characteristics; IEA:Ensembl.
DR GO; GO:0046544; P:development of secondary male sexual characteristics; IEA:Ensembl.
DR GO; GO:0006631; P:fatty acid metabolic process; ISS:BHF-UCL.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:0006549; P:isoleucine metabolic process; ISS:BHF-UCL.
DR GO; GO:0060397; P:JAK-STAT cascade involved in growth hormone signaling pathway; IDA:BHF-UCL.
DR GO; GO:0007595; P:lactation; IEA:Ensembl.
DR GO; GO:0019915; P:lipid storage; IEA:Ensembl.
DR GO; GO:0001889; P:liver development; IEA:Ensembl.
DR GO; GO:0001553; P:luteinization; IEA:Ensembl.
DR GO; GO:0001779; P:natural killer cell differentiation; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0045647; P:negative regulation of erythrocyte differentiation; IEA:Ensembl.
DR GO; GO:0006107; P:oxaloacetate metabolic process; ISS:BHF-UCL.
DR GO; GO:0048541; P:Peyer's patch development; IEA:Ensembl.
DR GO; GO:0042104; P:positive regulation of activated T cell proliferation; IEA:Ensembl.
DR GO; GO:0045579; P:positive regulation of B cell differentiation; IEA:Ensembl.
DR GO; GO:0051272; P:positive regulation of cellular component movement; IEA:Ensembl.
DR GO; GO:0045588; P:positive regulation of gamma-delta T cell differentiation; IEA:Ensembl.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IEA:Ensembl.
DR GO; GO:0045086; P:positive regulation of interleukin-2 biosynthetic process; IEA:Ensembl.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0040018; P:positive regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0032825; P:positive regulation of natural killer cell differentiation; IEA:Ensembl.
DR GO; GO:0045954; P:positive regulation of natural killer cell mediated cytotoxicity; IEA:Ensembl.
DR GO; GO:0032819; P:positive regulation of natural killer cell proliferation; IEA:Ensembl.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; ISS:UniProtKB.
DR GO; GO:0042448; P:progesterone metabolic process; IEA:Ensembl.
DR GO; GO:0038161; P:prolactin signaling pathway; ISS:UniProtKB.
DR GO; GO:0030155; P:regulation of cell adhesion; IEA:Ensembl.
DR GO; GO:0030856; P:regulation of epithelial cell differentiation; IEA:Ensembl.
DR GO; GO:0040014; P:regulation of multicellular organism growth; ISS:BHF-UCL.
DR GO; GO:0019218; P:regulation of steroid metabolic process; 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:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0070672; P:response to interleukin-15; IEA:Ensembl.
DR GO; GO:0070669; P:response to interleukin-2; IEA:Ensembl.
DR GO; GO:0070670; P:response to interleukin-4; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0006105; P:succinate metabolic process; ISS:BHF-UCL.
DR GO; GO:0033077; P:T cell differentiation in thymus; IEA:Ensembl.
DR GO; GO:0043029; P:T cell homeostasis; IEA:Ensembl.
DR GO; GO:0019530; P:taurine metabolic process; ISS:BHF-UCL.
DR GO; GO:0006366; P:transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0006573; P:valine metabolic process; ISS:BHF-UCL.
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; Complete proteome; Cytoplasm; Disease mutation;
KW DNA-binding; Dwarfism; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; SH2 domain; Transcription;
KW Transcription regulation.
FT CHAIN 1 787 Signal transducer and activator of
FT transcription 5B.
FT /FTId=PRO_0000182429.
FT DOMAIN 589 686 SH2.
FT REGION 232 321 Required for interaction with NMI.
FT MOD_RES 128 128 Phosphoserine.
FT MOD_RES 193 193 Phosphoserine.
FT MOD_RES 699 699 Phosphotyrosine; by HCK, JAK and PTK6.
FT VARIANT 130 130 A -> V (in dbSNP:rs2277619).
FT /FTId=VAR_052074.
FT VARIANT 630 630 A -> P (in GHII; affects activation by
FT growth hormone or interferon-gamma).
FT /FTId=VAR_018728.
FT VARIANT 646 646 F -> S (in GHII; transcriptionally
FT inactive).
FT /FTId=VAR_067368.
FT MUTAGEN 684 684 T->A: Abolishes interaction with INSR.
FT MUTAGEN 699 699 Y->F: Abolishes phosphorylation by HCK.
FT CONFLICT 230 230 A -> P (in Ref. 2; AAC50491).
SQ SEQUENCE 787 AA; 89866 MW; AA2F1CAB20955ACA CRC64;
MAVWIQAQQL QGEALHQMQA LYGQHFPIEV RHYLSQWIES QAWDSVDLDN PQENIKATQL
LEGLVQELQK KAEHQVGEDG FLLKIKLGHY ATQLQNTYDR CPMELVRCIR HILYNEQRLV
REANNGSSPA GSLADAMSQK HLQINQTFEE LRLVTQDTEN ELKKLQQTQE YFIIQYQESL
RIQAQFGPLA QLSPQERLSR ETALQQKQVS LEAWLQREAQ TLQQYRVELA EKHQKTLQLL
RKQQTIILDD ELIQWKRRQQ LAGNGGPPEG SLDVLQSWCE KLAEIIWQNR QQIRRAEHLC
QQLPIPGPVE EMLAEVNATI TDIISALVTS TFIIEKQPPQ VLKTQTKFAA TVRLLVGGKL
NVHMNPPQVK ATIISEQQAK SLLKNENTRN DYSGEILNNC CVMEYHQATG TLSAHFRNMS
LKRIKRSDRR GAESVTEEKF TILFESQFSV GGNELVFQVK TLSLPVVVIV HGSQDNNATA
TVLWDNAFAE PGRVPFAVPD KVLWPQLCEA LNMKFKAEVQ SNRGLTKENL VFLAQKLFNN
SSSHLEDYSG LSVSWSQFNR ENLPGRNYTF WQWFDGVMEV LKKHLKPHWN DGAILGFVNK
QQAHDLLINK PDGTFLLRFS DSEIGGITIA WKFDSQERMF WNLMPFTTRD FSIRSLADRL
GDLNYLIYVF PDRPKDEVYS KYYTPVPCES ATAKAVDGYV KPQIKQVVPE FVNASADAGG
GSATYMDQAP SPAVCPQAHY NMYPQNPDSV LDTDGDFDLE DTMDVARRVE ELLGRPMDSQ
WIPHAQS
//

MIM 245590
*RECORD*
*FIELD* NO
245590
*FIELD* TI
#245590 GROWTH HORMONE INSENSITIVITY WITH IMMUNODEFICIENCY
;;LARON SYNDROME DUE TO POSTRECEPTOR DEFECT;;
read moreGROWTH HORMONE INSENSITIVITY DUE TO POSTRECEPTOR DEFECT
*FIELD* TX
A number sign (#) is used with this entry because of evidence that at
least 1 form of postreceptor defect that causes growth hormone (GH;
139250) insensitivity results from mutation in the STAT5B gene (604260).
See 262500 for a form of growth hormone insensitivity caused by mutation
in the growth hormone receptor gene (GHR; 600946).

CLINICAL FEATURES

Laron et al. (1966) reported a form of genetic dwarfism (262500)
associated with high circulating growth hormone. Originally, they
assumed a faulty GH molecule, but subsequent investigations established
defective GH receptor (GHR; 600946), which precluded the binding of GH
as the cause. The defect in feedback on the pituitary, causing the
extensive GH oversecretion, was thought to be related to the lack of
IGF1 (147440), the synthetic product of GH-receptor interaction. The
defect in the growth hormone receptor was reflected by the deficiency of
serum growth hormone binding protein (GHBP), which is encoded by the GHR
gene. Buchanan et al. (1991) reported children in families originating
from Pakistan or India who showed typical features of Laron syndrome but
had normal levels of serum GHBP.

Laron et al. (1993) reported the cases of 3 sibs, born of first-cousin
Palestinian Arab parents, with Laron syndrome and normal serum GHBP who
underwent long-term treatment with biosynthetic IGF1 with results
indicating a post-GH receptor defect. Basal serum levels of growth
hormone were high and IGF1 low, but, in contradistinction to the classic
form of Laron syndrome, serum GHBP and insulin-like growth
factor-binding protein-3 (IGFBP3; 146732) were normal in these patients.
Laron et al. (1993) concluded from the results of short-term treatment
with human growth hormone and short- and long-term IGF1 administration
that the GH receptor and the signal transmission for IGFBP-3 synthesis
were normal but that a defect existed in the post-GH receptor mechanism
for the generation of IGF1. Treatment with IGF1 for 1 year increased the
growth velocity by 47 to 96% in the 2 older children. The sibs showed
the typical clinical features of Laron syndrome: they were very short
and obese, had acromicria, small genitalia (in the boys), and a
high-pitched voice. A prominent forehead was demonstrated in 1 patient.
It is perhaps significant that females on both sides of the family,
aunts of the 3 sibs, and the paternal grandmother were very short, being
less than 2 standard deviations below the mean. This may represent
heterozygous manifestation.

Kofoed et al. (2003) described a 16.5-year-old Argentinian girl, born of
first-cousin parents, who required care in a neonatal unit at birth due
to respiratory difficulties. She had poor weight gain and growth failure
during the first 3 years of life, and at 7 years of age, her height and
weight were below the fifth percentile. Continued respiratory
difficulties with increasing oxygen requirements led to lung biopsy,
which showed lymphoid interstitial pneumonia. At 8 years of age, she
presented with severe hemorrhagic varicella and subsequently had several
episodes of herpes zoster. Progressive worsening of her pulmonary
function resulted in a second lung biopsy at the age of 10 years from
which Pneumocystis carinii was isolated. A 12-month trial of growth
hormone therapy resulted in no improvement in growth rate. At the age of
16.5 years, her height was 117.8 cm (7.5 SD below the mean for age),
with normal body proportions and delayed secondary sex characteristics
(Tanner stage III pubertal development). She had a prominent forehead, a
saddle nose, and a high-pitched voice. There was no family history of
growth failure, and 2 unaffected sisters had normal stature.

Cohen et al. (2006) studied the then 20-year-old Argentinian patient
originally reported by Kofoed et al. (2003) and observed immune
dysregulation with decreased numbers of regulatory CD4+ (186940)/CD25
(IL2RA; 147730)-high T cells (Tregs). The patient's Tregs showed low
expression of FOXP3 (300292) and were impaired in their ability to
suppress proliferation of or to kill CD4+/CD25- cells. CD25 expression
was also reduced after IL2 (147680) stimulation, although IL2-mediated
upregulation of IL2RG (308380), perforin (PRF1; 170280), and CD154
(CD40LG; 300386) was normal. The immunologic phenotype of the patient's
heterozygous parents tended to be normal or intermediate.

Bernasconi et al. (2006) described a 16-year-old girl, born to
nonconsanguineous parents, who had generalized eczema and recurrent
infections of the skin and respiratory tract since birth, chronic
diarrhea from 2 years of age, and multiple episodes of herpetic
keratitis beginning at 10 years of age, with progressive loss of visual
acuity. When hospitalized at age 16 due to respiratory distress, she had
evidence of severe chronic hypoxemic lung disease as well as clinical
features of congenital GH deficiency, including prominent forehead,
saddle nose, and high-pitched voice, with no signs of pubertal onset.
She had a normal serum GH level with undetectable IFG1 or IGFB3, and
prolactin (176760) levels were persistently high. Immunologic analysis
revealed moderate T-cell lymphopenia, normal CD4/CD8 ratio, and very low
numbers of natural killer and gamma-delta T cells (see 186970), and the
T cells showed a chronically hyperactivated phenotype. In vitro T-cell
proliferation and IL2 signaling were impaired, and CD4+/CD25+ regulatory
T cells (Tregs) were significantly diminished.

MOLECULAR GENETICS

Freeth et al. (1997) identified 4 girls from 2 families with the Laron
syndrome phenotype but normal GHBP levels. No GHR gene mutations were
identified in 1 family. In the other family, the affected sibs, an
unaffected brother, and the father were heterozygous for a point
mutation (D152H; 600946.0021) within exon 6 of the GHR gene. In
addition, use of intron-9 polymorphisms to determine linkage to the GHR
gene implied inheritance of different maternal GHR alleles in the 2
affected girls of this family. It is unlikely, therefore, that the D152H
substitution alone could account for the Laron syndrome phenotype. To
identify the defect, endpoints of GH action, DNA synthesis, IGFBP3 mRNA,
and peptide production were examined in skin fibroblast cultures
established from 3 of the patients and 4 normal children. Whereas normal
fibroblasts incorporated [3H]thymidine dose dependently in response to
increments of GH, the patients' fibroblasts failed to respond
significantly above basal levels (P less than 0.01). In normal
fibroblasts, IGFBP3 mRNA and peptide increased maximally at 48 hours in
response to GH, as determined by ribonuclease protection assay, Western
ligand blotting, and radioimmunoassay. In comparison, the patients'
fibroblasts produced significantly less IGFBP3 peptide than normal
fibroblasts in response to GH, whereas IGFBP3 mRNA failed to increase
above basal levels. The findings suggested that GH insensitivity in
these children was not caused exclusively by GHR mutations, and was
probably caused by dysfunctional GHR signaling.

In a 16.5-year-old Argentinian girl with the clinical and biochemical
characteristics of GH insensitivity and immunodeficiency, Kofoed et al.
(2003) analyzed the GHR gene and protein but found no mutations and
normal serum GHBP levels. Noting that signal transduction involving the
GHR occurs by means of at least 3 well-established pathways, including
signal transducers and activators of transcription (STATs),
phosphatidylinositol-3 kinase (see PIK3R1; 171833), and
mitogen-activated protein kinase (see MAPK1; 176948) pathways, the
authors analyzed the STAT5B gene (604260) in this patient and identified
homozygosity for a missense mutation (A630P; 604260.0001). Kofoed et al.
(2003) concluded that the combined phenotype of growth hormone
insensitivity and immunodeficiency was consistent with the presence of a
defect in the JAK/STAT signaling system.

Hwa et al. (2005) reported a 16.4-year-old Turkish girl, born of
second-cousin parents, who had severe postnatal short stature and normal
to high levels of GH, normal GHBP levels, and extremely low serum IGF1,
which remained low after administration of GH. She also had a history of
pruritic skin lesions and recurrent pulmonary infections; CT scan of the
chest revealed primary idiopathic pulmonary fibrosis with diffuse lung
involvement, but biopsy was not performed because of a bleeding
diathesis due to defective thrombocyte aggregation. Evaluation at 15
years of age revealed that gross T cells, B cells, and natural killer
cells were within normal limits, as was the lymphoproliferative
response. Noting phenotypic similarities to the patient described by
Kofoed et al. (2003), Hwa et al. (2005) analyzed the STAT5B gene and
identified homozygosity for a 1-bp insertion (604260.0002) predicted to
severely truncate the protein with loss of the C terminus.

Vidarsdottir et al. (2006) described a 30-year-old man, born in the
Dutch Antilles of nonconsanguineous parents, who was diagnosed with
congenital ichthyosis (see 242300) at birth and had hemorrhagic
varicella at 16 years of age that was treated with acyclovir. He also
had short stature and delayed puberty with normal GH and GHBP levels, an
elevated plasma prolactin level, and extremely low levels of IGF1,
IGFBP3, and acid-labile subunit (ALS; 601489). Sequence analysis of the
STAT5B gene revealed homozygosity for a frameshift mutation
(604260.0003). The authors stated that unlike 2 previously reported
patients with STAT5B mutations (Kofoed et al., 2003; Hwa et al., 2005),
this patient had no history of pulmonary or immunologic problems.

In a 16-year-old girl with severe GH insensitivity and immunodeficiency,
Bernasconi et al. (2006) identified homozygosity for a nonsense mutation
in the STAT5B gene (604260.0004).

Hwa et al. (2007) reported 2 Kuwaiti sisters, born of consanguineous
parents, who had severe postnatal growth retardation with normal GH and
GHBP levels but abnormally low IGF1, IGFBP3, and ALS. Sequencing of the
GHR gene revealed no mutations, but both sibs were found to be
homozygous for a 1-bp deletion in the STAT5B gene (604260.0005). The
older sister, who was 3.9 years old, had been diagnosed with
bronchiectasis and interstitial pneumonitis; and her 2-year-old sister
had been diagnosed with idiopathic juvenile arthritis.

*FIELD* RF
1. Bernasconi, A.; Marino, R.; Ribas, A.; Rossi, J.; Ciaccio, M.;
Oleastro, M.; Ornani, A.; Paz, R.; Rivarola, M. A.; Zelazko, M.; Belgorosky,
A.: Characterization of immunodeficiency in a patient with growth
hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics 118:
e1584, 2006. Note: Electronic Article.

2. Buchanan, C. R.; Maheshwari, H. G.; Norman, M. R.; Morrell, D.
J.; Preece, M. A.: Laron-type dwarfism with apparently normal high
affinity serum growth hormone-binding protein. Clin. Endocr. 35:
179-185, 1991.

3. Cohen, A. C.; Nadeau, K. C.; Tu, W.; Hwa, V.; Dionis, K.; Bezrodnik,
L.; Teper, A.; Gaillard, M.; Heinrich, J.; Krensky, A. M.; Rosenfeld,
R. G.; Lewis, D. B.: Decreased accumulation and regulatory function
of CD4+CD25(high) T cells in human STAT5b deficiency. J. Immun. 177:
2770-2774, 2006.

4. Freeth, J. S.; Ayling, R. M.; Whatmore, A. J.; Towner, P.; Price,
D. A.; Norman, M. R.; Clayton, P. E.: Human skin fibroblasts as a
model of growth hormone (GH) action in GH receptor-positive Laron's
syndrome. Endocrinology 138: 55-61, 1997.

5. Hwa, V.; Camacho-Hubner, C.; Little, B. M.; David, A.; Metherell,
L. A.; El-Khatib, N.; Savage, M. O.; Rosenfeld, R. G.: Growth hormone
insensitivity and severe short stature in siblings: a novel mutation
at the exon 13-intron 13 junction of the STAT5b gene. Horm. Res. 68:
218-224, 2007.

6. Hwa, V.; Little, B.; Adiyaman, P.; Kofoed, E. M.; Pratt, K. L.;
Ocal, G.; Berberoglu, M.; Rosenfeld, R. G.: Severe growth hormone
insensitivity resulting from total absence of signal transducer and
activator of transcription 5b. J. Clin. Endocr. Metab. 90: 4260-4266,
2005.

7. Kofoed, E. M.; Hwa, V.; Little, B.; Woods, K. A.; Buckway, C. K.;
Tsubaki, J.; Pratt, K. L.; Bezrodnik, L.; Jasper, H.; Tepper, A.;
Heinrich, J. J.; Rosenfeld, R. G.: Growth hormone insensitivity associated
with a STAT5b mutation. New Eng. J. Med. 349: 1139-1147, 2003.

8. Laron, Z.; Klinger, B.; Eshet, R.; Kaneti, H.; Karasik, A.; Silbergeld,
A.: Laron syndrome due to a post-receptor defect: response to IGF-1
treatment. Isr. J. Med. Sci. 29: 757-763, 1993.

9. Laron, Z.; Pertzelan, A.; Mannheimer, S.: Genetic pituitary dwarfism
with high serum concentration of growth hormone: a new inborn error
of metabolism? Isr. J. Med. Sci. 2: 152-155, 1966.

10. Vidarsdottir, S.; Walenkamp, M. J. E.; Pereira, A. M.; Karperien,
M.; van Doorn, J.; van Duyvenvoorde, H. A.; White, S.; Bruening, M.
H.; Roelfsema, F.; Kruithof, M. F.; van Dissel, J.; Janssen, R.; Wit,
J. M.; Romijn, J. A.: Clinical and biochemical characteristics of
a male patient with a novel homozygous STAT5b mutation. J. Clin.
Endocr. Metab. 91: 3482-3485, 2006.

*FIELD* CN
Marla J. F. O'Neill - updated: 7/17/2007
Marla J. F. O'Neill - reorganized: 7/17/2007
Victor A. McKusick - updated: 10/10/2003
John A. Phillips, III - updated: 4/8/1997

*FIELD* CD
Victor A. McKusick: 4/15/1994

*FIELD* ED
terry: 10/12/2010
carol: 7/18/2007
terry: 7/17/2007
carol: 7/17/2007
carol: 7/5/2007
carol: 10/27/2003
tkritzer: 10/21/2003
terry: 10/10/2003
terry: 6/5/2001
jlewis: 7/27/1999
jenny: 4/21/1997
jenny: 4/8/1997
mimadm: 4/18/1994
carol: 4/15/1994

MIM 604260
*RECORD*
*FIELD* NO
604260
*FIELD* TI
*604260 SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 5B; STAT5B
STAT5B/RARA FUSION GENE, INCLUDED
read more*FIELD* TX

DESCRIPTION

STAT5A (601511) and STAT5B are activated in response to a variety of
cytokines (Wang et al., 1996).

CLONING

Ambrosio et al. (2002) cloned the human STAT5B gene. They identified 2
alternatively spliced STAT5B transcripts that differ only in their
noncoding promoter sequences. The deduced 787-amino acid STAT5B protein
has an N-terminal DNA-binding domain, followed by a 4-helix bundle, a
DNA-binding specificity domain, a connector region, an SH2 domain, and a
C-terminal transactivation domain. RT-PCR detected the STAT5B transcript
containing promoter I in all tissues and cell lines examined.
Transcripts containing promoter II were highly expressed in placenta and
could be detected at weaker levels in spleen, brain, and heart, as well
as in some cell lines.

Wang et al. (1996) demonstrated that carboxy-truncated variant Stat5a
and Stat5b proteins of 77 and 80 kD, respectively, naturally occur in
mouse. These truncated Stat5a and Stat5b forms are derived from
incompletely spliced Stat5a and Stat5b transcripts.

By Northern blot analysis, Miyoshi et al. (2001) found that mouse Stat5b
is expressed from 2 promoters. Expression from the distal promoter was
ubiquitous, whereas expression from the proximal promoter was restricted
to liver, muscle, and mammary tissue.

GENE FUNCTION

Wang et al. (1996) showed that the truncated mouse Stat5a and Stat5b
proteins are inducibly tyrosine phosphorylated in the response to
several cytokines. These truncated Stat5 proteins form heterodimers with
both the full-length wildtype Stat5a and Stat5b proteins. Wang et al.
(1996) demonstrated that recombinant truncated forms of Stat5a and
Stat5b can be tyrosine phosphorylated and can bind to DNA. The tyrosine
phosphorylation of the carboxy-truncated forms was considerably more
stable than that of the wildtype Stat5a and Stat5b proteins.
Overexpression of a carboxy-truncated Stat5a protein in cells resulted
in the specific inhibition of the IL3 (147740)-induced transcriptional
activation of the oncostatin M gene (OSM; 165095) and the
cytokine-inducible SH2 domain-encoding gene (Cis), both of which have
been shown to be normally regulated by Stat5a. Although the truncated
Stat5a protein dominantly suppressed the induction of these genes, no
effects on cell proliferation were observed. Wang et al. (1996) stated
that their results demonstrate the natural existence of potential
dominantly suppressive variants of Stat5a and Stat5b, and implicate the
carboxyl domains of Stat5a and Stat5b proteins in transcriptional
regulation and functions related to dephosphorylation.

Boucheron et al. (1998) examined the DNA-binding domains of mouse Stat5a
and Stat5b and determined that the difference in their DNA-binding
specificities depends on a critical glycine residue in Stat5b and a
critical glutamic residue at a similar position in Stat5a.

Mak et al. (2002) studied the role of STAT5 as a component of the
differentiation of endometrium in response to ovarian hormone
stimulation in vivo. The abundance and subcellular distribution of STAT5
in endometrial stromal cells after a decidualization stimulus of cAMP
plus medroxyprogesterone acetate (MPA) had been investigated in vitro.
Western blot analysis revealed an increase in the apparent abundance of
STAT5A and STAT5B in the cytosolic and nuclear fractions at 2, 3, and 4
days after stimulation. The potential functional relevance of this
increase in STAT5 was suggested by the ability of transiently
transfected STAT5A or STAT5B to significantly enhance the response of
the decidual PRL (176760) promoter to cAMP/MPA acetate and attenuation
of the response to cAMP/MPA by dominant-negative STAT5. Mak et al.
(2002) concluded that regulated expression of STAT5 is therefore a
component of decidual differentiation of human endometrial stromal cells
and contributes significantly to activation of the decidual PRL
promoter. Alteration of this process by an antiphospholipid antibody
component suggested decidual differentiation as a potential clinical
target in recurrent early miscarriages.

In the Drosophila male germline, local activation of the Janus
kinase-signal transducer and activator of transcription (Jak-STAT)
pathway maintains stem cells; germline stem cells lacking Jak-STAT
signaling differentiate into spermatogonia without self-renewal. By
conditionally manipulating Jak-STAT signaling using a
temperature-sensitive allele of Stat92e, the Drosophila homolog of
STAT5B, Brawley and Matunis (2004) demonstrated that spermatogonia that
have initiated differentiation and are undergoing limited mitotic
(transit-amplifying) divisions can repopulate the niche and revert to
stem cell identity. Thus, Brawley and Matunis (2004) have shown that in
the appropriate microenvironment, transit-amplifying cells
dedifferentiate, becoming functional stem cells during tissue
regeneration.

Wawersik et al. (2005) showed that the JAK/STAT pathway provides a
sex-specific signal from the soma to the germline in Drosophila
embryonic gonads. The somatic gonad expresses a JAK/STAT ligand,
'unpaired' (upd), in a male-specific manner, and activates the JAK/STAT
pathway in male germ cells at the time of gonad formation. Furthermore,
the JAK/STAT pathway is necessary for male-specific germ cell behavior
during early gonad development, and is sufficient to activate aspects of
male germ cell behavior in female germ cells. Wawersik et al. (2005)
found that Drosophila Stat92e was upregulated specifically in male, but
not female, germ cells at the time of gonad formation. This reflects
male-specific activation of the JAK/STAT pathway because the activated
form of Stat92e (phosphorylated Stat92e) was also detected only in male
germ cells, and JAK activity was necessary and sufficient for Stat92e
expression. Wawersik et al. (2005) concluded that their findings
provided direct evidence that the JAK/STAT pathway mediates a key signal
from the somatic gonad that regulates male germline sexual development.

Vignudelli et al. (2010) found that overexpression of ZFP36L1 (601064)
in human CD34 (142230)-positive cord blood-derived stem/progenitor cells
inhibited their erythroid differentiation and colony formation, which
appeared to be due to downregulation of STAT5B protein levels through
degradation of STAT5B mRNA. Overexpression of ZFP36 (190700) also
inhibited erythroid differentiation, and overexpression of both ZFP36
and ZFP36L1 had a cumulative effect. Both ZFP36 and ZFP36L1 directly
bound a canonical AU-rich element II in the 3-prime UTR of STAT5B mRNA.
Vignudelli et al. (2010) concluded that ZFP36L1 negatively regulates
erythroid differentiation by interfering with the STAT5B pathway in
human hematopoietic stem cells.

GENE STRUCTURE

Ambrosio et al. (2002) determined that the STAT5B gene contains 19
exons. It has 2 alternate first exons, 1a and 1b, which are separated by
about 1.3 kb. A CpG island covers exon 1a and extends into the 5-prime
flanking region. Exon 2 contains the ATG start codon.

Miyoshi et al. (2001) determined that the mouse Stat5b gene contains 20
exons and spans more than 50 kb. The translation initiation codon is in
exon 2, and the stop codon is in exon 19. Stat5b has 2 promoters
separated by more than 20 kb.

Crispi et al. (2004) determined that both the STAT5A and STAT5B genes
lack TATA and CAAT elements, but both have binding sites for
transcription factors common in TATA-less promoters. Using a reporter
assay, they determined that gene fragments containing the CpG islands
were the most transcriptionally active fragments. Sp1 (189906) enhanced
expression of the basal promoters, and DNA methylation interfered with
Sp1-induced transcription. Cross-species sequence comparison identified
a bidirectional negative cis-acting regulatory element in the STAT5
intergenic region.

MAPPING

By FISH, Lin et al. (1996) mapped the STAT5A (601511) and STAT5B genes
to 17q11.2. In their FISH analysis, Arnould et al. (1999) found that the
STAT5B and RARA genes are very close to each other in 17q21.1-q21.2.
Ambrosio et al. (2002) determined that the STAT5A and STAT5B genes are
in an inverted orientation, with their 5-prime ends about 11 kb apart.

Miyoshi et al. (2001) mapped the mouse Stat5b gene to chromosome 11. The
promoters of the Stat5a and Stat5b genes are located head to head and
are separated by 10 kb. The order and orientation of genes at this
locus, Ptrf (603189)--Stat3 (102582)--Stat5a--Stat5b--Lgp1
(608587)--Hcrt (602358), are identical in the syntenic region of human
chromosome 17q21.

CYTOGENETICS

Acute promyelocytic leukemia (APL) exhibits a characteristic t(15;17)
translocation that fuses the promyelocytic leukemia gene (PML; 102578)
on 15q22 to the retinoic acid receptor-alpha gene (RARA; 180240) on
17q12-q21.1. In a small subset of acute promyelocytic-like leukemias
(APLL), RARA is fused to a different partner: the promyelocytic leukemia
zinc finger gene (PLZF; 176797) on 11q23, the nucleophosmin gene (NPM1;
164040) on 5q35, or the nuclear mitotic apparatus-1 gene (NUMA1; 164009)
on 11q13. Arnould et al. (1999) reported the molecular characterization
of a RARA gene rearrangement in a patient with APLL and demonstrated
that the partner fused to RARA was the STAT5B gene, which belongs to the
Janus kinase (JAK)/STAT signaling pathway. Remarkably, the STAT5B
component of the chimeric protein was delocalized from the cytoplasm to
the nucleus, where it displayed a microspeckled pattern. Therefore,
unusual features of this APLL might result from dysregulation of the
JAK/STAT5 signal transducing pathways in the leukemic cells of the
patient. This was the first example of a human tumor bearing a
structurally abnormal STAT gene.

MOLECULAR GENETICS

Kofoed et al. (2003) noted that signal transduction involving the growth
hormone receptor (GHR; 600946) occurs by means of at least 3
well-established pathways: STAT, phosphatidylinositol-3 kinase (see
PIK3R1, 171833), and mitogen-activated protein kinase (see MAPK1,
176948) pathways. Collectively, these pathways mediate the
growth-promoting and metabolic actions of growth hormone (GH; 139250).
Kofoed et al. (2003) described a patient with the clinical and
biochemical characteristics of growth hormone insensitivity (245590), a
normal GHR gene, and a homozygous ala630-to-pro mutation (A630P;
604260.0001) in the STATB gene. The patient had a combined phenotype of
GH insensitivity and immunodeficiency consistent with the presence of a
defect in the JAK/STAT system.

Cohen et al. (2006) studied the patient originally reported by Kofoed et
al. (2003) and observed immune dysregulation with decreased numbers of
regulatory CD4+ (186940)/CD25 (IL2RA; 147730)-high T cells (Tregs). The
patient's Tregs showed low expression of FOXP3 (300292) and were
impaired in their ability to suppress proliferation of or to kill
CD4+/CD25- cells. CD25 expression was also reduced after IL2 (147680)
stimulation, although IL2-mediated upregulation of IL2RG (308380),
perforin (PRF1; 170280), and CD154 (CD40LG; 300386) was normal. The
immunologic phenotype of the patient's heterozygous parents tended to be
normal or intermediate.

In a 16.4-year-old Turkish girl with postnatal growth retardation and
insensitivity to growth hormone, who also had recurrent pulmonary
infections and a bleeding diathesis due to defective thrombocyte
aggregation, Hwa et al. (2005) identified homozygosity for a 1-bp
insertion in the STAT5B gene (604260.0002).

In a 30-year-old man born in the Dutch Antilles who had short stature
and delayed puberty with normal GH and GHBP levels, an elevated plasma
prolactin (176760) level, and extremely low levels of IGF1, IGFBP3
(146732), and acid-labile subunit (ALS; 601489), Vidarsdottir et al.
(2006) identified homozygosity for a 1-bp insertion in the STAT5B gene
(604260.0003). The authors stated that the patient was diagnosed with
congenital ichthyosis at birth (see 242300) and had hemorrhagic
varicella at 16 years of age, but had no history of pulmonary or
immunologic problems.

In a 16-year-old girl with severe postnatal growth failure, GH
insensitivity, and immunodeficiency, Bernasconi et al. (2006) identified
homozygosity for a nonsense mutation in the STAT5B gene (604260.0004).
Immunologic analysis revealed a moderate T-cell lymphopenia, normal
CD4/CD8 ratio, and very low numbers of natural killer and gamma-delta
(see 186970) T cells, and the T cells had a chronically hyperactivated
phenotype. In vitro T-cell proliferation and interleukin-2 (147680)
signaling were impaired, and CD4+/CD25+ regulatory T cells (Tregs) were
significantly diminished. Bernasconi et al. (2006) concluded that STAT5B
is a key protein for T-cell function in humans.

In 2 Kuwaiti sisters with severe postnatal growth retardation, normal GH
and GHBP levels, and no mutation in the GH receptor gene, Hwa et al.
(2007) identified homozygosity for a 1-bp deletion in the STAT5B gene
(604260.0005). The 3.9-year-old sister had recently been diagnosed with
bronchiectasis and interstitial pneumonitis, and her 2-year-old sister
had been diagnosed with idiopathic juvenile arthritis.

ANIMAL MODEL

STAT5 is activated in a broad spectrum of human hematologic
malignancies. Using a genetic approach, Schwaller et al. (2000)
addressed whether activation of STAT5 is necessary for the myelo- and
lymphoproliferative disease induced by the TEL (600618)/JAK2 (147796)
fusion gene. Whereas mice transplanted with bone marrow transduced with
retrovirus expressing TEL/JAK2 developed a rapidly fatal myelo- and
lymphoproliferative syndrome, reconstitution with bone marrow derived
from Stat5a/b-deficient mice expressing TEL/JAK2 did not induce disease.
Disease induction in the Stat5a/b-deficient background was rescued with
a bicistronic retrovirus encoding TEL/JAK2 and Stat5a. Furthermore,
myeloproliferative disease was induced by reconstitution with bone
marrow cells expressing a constitutively active mutant, Stat5a, or a
single Stat5a target, murine Osm. These data defined a critical role for
STAT5A/B and OSM in the pathogenesis of TEL/JAK2 disease.

Snow et al. (2003) observed that a subset of mice deficient in both
Stat5a and Stat5b had dramatic alterations in several bone marrow
progenitor populations, along with cellular infiltration of colon,
liver, and kidney and early death. The pathology and increased mortality
in these mice were abrogated when Rag1 (179615) was also deleted. The
phenotype was similar to that in mice defective in Il2 (147680)
signaling and correlated with a reduction in the number of Cd4
(186940)-positive/Cd25 (IL2RA; 147730)-positive regulatory T cells. Snow
et al. (2003) concluded that STAT5 is critical for maintenance of
tolerance in vivo and that STAT5 is probably activated by IL2R.

Cui et al. (2004) conditionally deleted the 110-kb Stat5 locus, which
spans both the Stat5a and Stat5b genes, to study the functions of the
Stat5 genes during mouse mammary gland development. Loss of the Stat5
genes prior to pregnancy prevented epithelial proliferation and
differentiation. Deletion of Stat5 during pregnancy, after mammary
epithelium had entered Stat5-mediated differentiation, resulted in
premature cell death, indicating that mammary epithelial cell
proliferation, differentiation, and survival require Stat5.

Yao et al. (2006) compared mice with a complete deletion of Stat5a and
Stat5b (Stat5 -/-) with mice having an N-terminally truncated, partially
functional Stat5 protein (Stat5delN) and mice lacking Il7r (146661),
Jak3 (600173), or the common gamma chain, Il2rg (308380). Stat5 -/- mice
died before or shortly after birth. Examination of day-18.5 Stat5 -/-
embryos showed a severe combined immunodeficiency (SCID; see 601457)
phenotype with significantly fewer thymocytes and splenocytes than
wildtype controls. The thymocyte deficit in Stat5 -/- embryos was
similar in magnitude to that in Il7r- or Il2rg-deficient embryos,
whereas Stat5delN embryos had significantly more thymocytes. The
splenocyte reduction in Stat5 -/- embryos was more severe than that in
Il7r- or IL2rg-deficient mice. B-cell proportions were particularly low
in Stat5 -/- embryos compared with controls, similar to Il7r -/- mice.
Tcra (see 186880) and Tcrb (see 186930) rearrangement was normal in
Stat5 -/- mice, but Tcrg (see 186970) rearrangement was defective. As in
Jak3 -/- mice, there was a marked reduction in CD8-positive T cells. Yao
et al. (2006) concluded that STAT5 deficiency results in SCID, similar
in many respects to what occurs in IL7R, JAK3, or IL2RG deficiency.

*FIELD* AV
.0001
GROWTH HORMONE INSENSITIVITY WITH IMMUNODEFICIENCY
STAT5B, ALA630PRO

In a 16.5-year-old Argentinian girl with short stature and growth
hormone insensitivity (245590), Kofoed et al. (2003) identified
homozygosity for a G-to-C transversion in exon 15 of the STAT5B gene,
result in an ala630-to-pro (A630P) substitution. Both parents were
heterozygous for the mutation; there was no family history of growth
failure, and the girl's younger sisters were of normal stature. The
patient also had recurrent pulmonary infections; biopsy revealed
lymphoid interstitial pneumonia and Pneumocystis carinii was isolated
from the tissue. Kofoed et al. (2003) concluded that the combined
phenotype of growth hormone insensitivity and immunodeficiency was
consistent with the presence of a defect in the JAK/STAT signaling
system.

Fang et al. (2006) studied the molecular mechanisms underlying the
growth hormone (GH; 139250) insensitivity and IGF1 (147440) deficiency
caused by A630P-mutated STAT5B. The A630P mutation disrupts the SRC
homology 2 (SH2) architecture such that mutant STAT5B most likely cannot
dock to phosphotyrosines on ligand-activated receptors, and stable
interactions with DNA are prevented. Fang et al. (2006) concluded that
because A630P-mutant STAT5B is an inefficient signal transducer and
transcription factor, the detrimental impact on signaling pathways
important for normal growth and immunity explains, in part, the complex
clinical phenotype of GH insensitivity and immune dysfunction.

.0002
GROWTH HORMONE INSENSITIVITY WITH IMMUNODEFICIENCY
STAT5B, 1-BP INS, 1191G

In a 16.4-year-old Turkish girl with postnatal growth retardation and
insensitivity to growth hormone (245590), born of second-cousin parents,
Hwa et al. (2005) identified homozygosity for a 1-bp insertion
(1191insG) in exon 10 of the STAT5B gene, resulting in an asp398-to-glu
(N398E) substitution and predicted to cause a stop codon 15 amino acids
downstream with loss of the C terminus. The mutation was not found in 50
controls. The patient also had recurrent pulmonary infections and a
bleeding diathesis due to defective thrombocyte aggregation.

.0003
GROWTH HORMONE INSENSITIVITY WITH IMMUNODEFICIENCY
STAT5B, 1-BP INS, 1102C

In a 30-year-old man, born in the Dutch Antilles of nonconsanguineous
parents, who had short stature and delayed puberty with growth hormone
insensitivity (245590), Vidarsdottir et al. (2006) identified
homozygosity for a 1-bp insertion (1102insC) in the STAT5b gene, causing
a frameshift predicted to result in a truncated protein lacking most of
the DNA-binding domain and the SH2 domain. The patient's parents,
brother, and sister were all heterozygous carriers of the mutation. The
authors stated that the patient was diagnosed with congenital ichthyosis
at birth (see 242300) and had hemorrhagic varicella at 16 years of age,
but had no history of pulmonary or immunologic problems.

.0004
GROWTH HORMONE INSENSITIVITY WITH IMMUNODEFICIENCY
STAT5B, ARG152TER

In a 16-year-old girl with severe postnatal growth failure, growth
hormone insensitivity, and immunodeficiency (245590), Bernasconi et al.
(2006) identified homozygosity for a C-T transition in exon 5 of the
STAT5B gene, resulting in an arg152-to-ter (R152X) substitution
predicted to cause complete absence of protein expression. The patient's
parents and brother were heterozygous for the mutation.

.0005
GROWTH HORMONE INSENSITIVITY WITH IMMUNODEFICIENCY
STAT5B, 1-BP DEL, EXON 13/INTRON 13 JUNCTION

In 2 Kuwaiti sisters, born of consanguineous parents, who had severe
postnatal growth retardation but normal growth hormone (139250) and
growth hormone-binding protein (see 600946) levels, Hwa et al. (2007)
identified homozygosity for the deletion of a single G at the exon
13/intron 13 junction of the STAT5B gene, predicted to cause a
frameshift and alternative splicing. The parents, who were of normal
stature, were heterozygous for the mutation. The older sister, aged 3.9
years, had recently been diagnosed with bronchiectasis and interstitial
pneumonitis, and her 2-year-old sister had been diagnosed with
idiopathic juvenile arthritis.

*FIELD* RF
1. Ambrosio, R.; Fimiani, G.; Monfregola, J.; Sanzari, E.; De Felice,
N.; Salerno, M. C.; Pignata, C.; D'Urso, M.; Ursini, M. V.: The structure
of human STAT5A and STAT5B genes reveals two regions of nearly identical
sequence and an alternative tissue specific STAT5B promoter. Gene 285:
311-318, 2002.

2. Arnould, C.; Philippe, C.; Bourdon, V.; Gregoire, M. J.; Berger,
R.; Jonveaux, P.: The signal transducer and activator of transcription
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3. Bernasconi, A.; Marino, R.; Ribas, A.; Rossi, J.; Ciaccio, M.;
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A.: Characterization of immunodeficiency in a patient with growth
hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics 118:
e1584, 2006. Note: Electronic Article.

4. Boucheron, C.; Dumon, S.; Santos, S. C. R.; Moriggl, R.; Hennighausen,
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5. Brawley, C.; Matunis, E.: Regeneration of male germline stem cells
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6. Cohen, A. C.; Nadeau, K. C.; Tu, W.; Hwa, V.; Dionis, K.; Bezrodnik,
L.; Teper, A.; Gaillard, M.; Heinrich, J.; Krensky, A. M.; Rosenfeld,
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7. Crispi, S.; Sanzari, E.; Monfregola, J.; De Felice, N.; Fimiani,
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27-34, 2004.

8. Cui, Y.; Riedlinger, G.; Miyoshi, K.; Tang, W.; Li, C.; Deng, C.-X.;
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mammary epithelium during pregnancy reveals distinct functions in
cell proliferation, survival, and differentiation. Molec. Cell. Biol. 24:
8037-8047, 2004.

9. Fang, P.; Kofoed, E. M.; Little, B. M.; Wang, X.; Ross, R. J. M.;
Frank, S. J.; Hwa, V.; Rosenfeld, R. G.: A mutant signal transducer
and activator of transcription 5b, associated with growth hormone
insensitivity and insulin-like growth factor-I deficiency, cannot
function as a signal transducer or transcription factor. J. Clin.
Endocr. Metab. 91: 1526-1534, 2006.

10. Hwa, V.; Camacho-Hubner, C.; Little, B. M.; David, A.; Metherell,
L. A.; El-Khatib, N.; Savage, M. O.; Rosenfeld, R. G.: Growth hormone
insensitivity and severe short stature in siblings: a novel mutation
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218-224, 2007.

11. Hwa, V.; Little, B.; Adiyaman, P.; Kofoed, E. M.; Pratt, K. L.;
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13. Lin, J.-X.; Mietz, J.; Modi, W. S.; John, S.; Leonard, W. J.:
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14. Mak, I. Y. H.; Brosens, J. J.; Christian, M.; Hills, F. A.; Chamley,
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15. Miyoshi, K.; Cui, Y.; Riedlinger, G.; Robinson, P.; Lehoczky,
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150-155, 2001.

16. Schwaller, J.; Parganas, E.; Wang, D.; Cain, D.; Aster, J. C.;
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18. Vidarsdottir, S.; Walenkamp, M. J. E.; Pereira, A. M.; Karperien,
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19. Vignudelli, T.; Selmi, T.; Martello, A.; Parenti, S.; Grande,
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22. Yao, Z.; Cui, Y.; Watford, W. T.; Bream, J. H.; Yamaoka, K.; Hissong,
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*FIELD* CN
Patricia A. Hartz - updated: 12/22/2011
Marla J. F. O'Neill - updated: 7/17/2007
John A. Phillips, III - updated: 5/14/2007
Paul J. Converse - updated: 3/9/2007
Paul J. Converse - updated: 5/5/2006
Paul J. Converse - updated: 3/16/2006
Ada Hamosh - updated: 8/15/2005
Patricia A. Hartz - updated: 10/5/2004
Ada Hamosh - updated: 6/8/2004
Patricia A. Hartz - updated: 4/1/2004
Victor A. McKusick - updated: 10/10/2003
John A. Phillips, III - updated: 2/4/2003
Stylianos E. Antonarakis - updated: 10/11/2000
Patti M. Sherman - updated: 6/26/2000

*FIELD* CD
Victor A. McKusick: 10/26/1999

*FIELD* ED
mgross: 10/04/2013
mgross: 1/11/2012
terry: 12/22/2011
alopez: 6/2/2009
terry: 7/17/2007
carol: 7/17/2007
alopez: 5/14/2007
mgross: 3/14/2007
terry: 3/9/2007
mgross: 5/8/2006
terry: 5/5/2006
mgross: 4/4/2006
terry: 3/16/2006
alopez: 8/19/2005
terry: 8/15/2005
mgross: 10/5/2004
alopez: 6/9/2004
terry: 6/8/2004
mgross: 4/16/2004
terry: 4/1/2004
carol: 10/27/2003
tkritzer: 10/21/2003
terry: 10/10/2003
cwells: 2/4/2003
mgross: 10/11/2000
mcapotos: 7/14/2000
psherman: 6/26/2000
mgross: 10/26/1999