Full text data of ERRFI1
ERRFI1
(MIG6)
[Confidence: low (only semi-automatic identification from reviews)]
ERBB receptor feedback inhibitor 1 (Mitogen-inducible gene 6 protein; MIG-6)
ERBB receptor feedback inhibitor 1 (Mitogen-inducible gene 6 protein; MIG-6)
UniProt
Q9UJM3
ID ERRFI_HUMAN Reviewed; 462 AA.
AC Q9UJM3; B2RDX9; Q9NTG9; Q9UD05;
DT 27-JAN-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-2000, sequence version 1.
DT 22-JAN-2014, entry version 101.
DE RecName: Full=ERBB receptor feedback inhibitor 1;
DE AltName: Full=Mitogen-inducible gene 6 protein;
DE Short=MIG-6;
GN Name=ERRFI1; Synonyms=MIG6;
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], AND SUBCELLULAR LOCATION.
RX PubMed=7641805; DOI=10.1006/excr.1995.1261;
RA Wick M., Buerger C., Funk M., Mueller R.;
RT "Identification of a novel mitogen-inducible gene (mig-6): regulation
RT during G1 progression and differentiation.";
RL Exp. Cell Res. 219:527-535(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Van Laar T., Schouten T., van der Eb A.J., Terleth C.;
RT "The gene for Mig-6 is regulated by methylmethanesulphonate and shows
RT high expression in the liver.";
RL Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 302-462.
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461, 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 [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-251 AND SER-461, AND
RP MASS 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 [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-251 AND SER-461, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [12]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 325-364 IN COMPLEX WITH EGFR,
RP SUBUNIT, MUTAGENESIS OF MET-346; PHE-352 AND TYR-358, AND DOMAIN.
RX PubMed=18046415; DOI=10.1038/nature05998;
RA Zhang X., Pickin K.A., Bose R., Jura N., Cole P.A., Kuriyan J.;
RT "Inhibition of the EGF receptor by binding of MIG6 to an activating
RT kinase domain interface.";
RL Nature 450:741-744(2007).
CC -!- FUNCTION: Negative regulator of EGFR signaling in skin
CC morphogenesis. Acts as a negative regulator for several EGFR
CC family members, including ERBB2, ERBB3 and ERBB4. Inhibits EGFR
CC catalytic activity by interfering with its dimerization. Inhibits
CC autophosphorylation of EGFR, ERBB2 and ERBB4. Important for normal
CC keratinocyte proliferation and differentiation. Plays a role in
CC modulating the response to steroid hormones in the uterus.
CC Required for normal response to progesterone in the uterus and for
CC fertility. Mediates epithelial estrogen responses in the uterus by
CC regulating ESR1 levels and activation. Important for regulation of
CC endometrium cell proliferation. Important for normal prenatal and
CC perinatal lung development (By similarity).
CC -!- SUBUNIT: Interacts with ERBB2 (By similarity). Interacts with
CC EGFR.
CC -!- INTERACTION:
CC O14757:CHEK1; NbExp=2; IntAct=EBI-2941912, EBI-974488;
CC P00533:EGFR; NbExp=8; IntAct=EBI-2941912, EBI-297353;
CC P62993:GRB2; NbExp=8; IntAct=EBI-2941912, EBI-401755;
CC P31947:SFN; NbExp=3; IntAct=EBI-2941912, EBI-476295;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane; Peripheral
CC membrane protein; Cytoplasmic side (By similarity). Nucleus (By
CC similarity). Note=Associated with the plasma membrane of basal
CC skin keratinocytes. Translocates into the nucleus of
CC differentiating suprabasal keratinocytes (By similarity).
CC -!- INDUCTION: Levels are very low in quiescent cells. Up-regulated by
CC mitogens.
CC -!- DOMAIN: The EGFR-binding region prevents binding of a cyclin-like
CC activator to the EGFR kinase domain, and thereby keeps EGFR in an
CC inactive conformation. Also maintains EGFR in an inactive
CC conformation by preventing formation of an asymmetric homodimer.
CC -!- SIMILARITY: Belongs to the MIG6 family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ERRFI1ID44147ch1p36.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AJ276373; CAC20426.1; -; mRNA.
DR EMBL; AL034417; CAB52551.1; -; Genomic_DNA.
DR EMBL; AK315718; BAG38076.1; -; mRNA.
DR EMBL; CH471130; EAW71593.1; -; Genomic_DNA.
DR EMBL; BC025337; AAH25337.1; -; mRNA.
DR EMBL; AL137274; CAB70672.1; -; mRNA.
DR PIR; T46346; T46346.
DR RefSeq; NP_061821.1; NM_018948.3.
DR UniGene; Hs.605445; -.
DR PDB; 2RF9; X-ray; 3.50 A; C/D=315-374.
DR PDB; 2RFD; X-ray; 3.60 A; C/D=340-364.
DR PDB; 2RFE; X-ray; 2.90 A; E/F=325-364.
DR PDB; 4I21; X-ray; 3.37 A; C/D=315-374.
DR PDBsum; 2RF9; -.
DR PDBsum; 2RFD; -.
DR PDBsum; 2RFE; -.
DR PDBsum; 4I21; -.
DR ProteinModelPortal; Q9UJM3; -.
DR SMR; Q9UJM3; 335-364.
DR DIP; DIP-42379N; -.
DR IntAct; Q9UJM3; 18.
DR MINT; MINT-1591605; -.
DR STRING; 9606.ENSP00000366702; -.
DR PhosphoSite; Q9UJM3; -.
DR DMDM; 27923810; -.
DR PaxDb; Q9UJM3; -.
DR PRIDE; Q9UJM3; -.
DR DNASU; 54206; -.
DR Ensembl; ENST00000377482; ENSP00000366702; ENSG00000116285.
DR GeneID; 54206; -.
DR KEGG; hsa:54206; -.
DR UCSC; uc001aoz.3; human.
DR CTD; 54206; -.
DR GeneCards; GC01M008064; -.
DR HGNC; HGNC:18185; ERRFI1.
DR HPA; HPA027206; -.
DR MIM; 608069; gene.
DR neXtProt; NX_Q9UJM3; -.
DR PharmGKB; PA142671904; -.
DR eggNOG; NOG147618; -.
DR HOGENOM; HOG000234207; -.
DR HOVERGEN; HBG031710; -.
DR InParanoid; Q9UJM3; -.
DR OMA; KPAIRIS; -.
DR PhylomeDB; Q9UJM3; -.
DR SignaLink; Q9UJM3; -.
DR ChiTaRS; ERRFI1; human.
DR EvolutionaryTrace; Q9UJM3; -.
DR GeneWiki; ERRFI1; -.
DR GenomeRNAi; 54206; -.
DR NextBio; 56530; -.
DR PRO; PR:Q9UJM3; -.
DR ArrayExpress; Q9UJM3; -.
DR Bgee; Q9UJM3; -.
DR CleanEx; HS_ERRFI1; -.
DR Genevestigator; Q9UJM3; -.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0031234; C:extrinsic to cytoplasmic side of plasma membrane; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005100; F:Rho GTPase activator activity; TAS:ProtInc.
DR GO; GO:0048286; P:lung alveolus development; ISS:UniProtKB.
DR GO; GO:0060428; P:lung epithelium development; ISS:UniProtKB.
DR GO; GO:0060426; P:lung vasculature development; ISS:UniProtKB.
DR GO; GO:0007175; P:negative regulation of epidermal growth factor-activated receptor activity; IDA:UniProtKB.
DR GO; GO:0031953; P:negative regulation of protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0045616; P:regulation of keratinocyte differentiation; ISS:UniProtKB.
DR GO; GO:0006950; P:response to stress; TAS:ProtInc.
DR GO; GO:0043589; P:skin morphogenesis; ISS:UniProtKB.
DR InterPro; IPR015116; Cdc42_binding_dom_like.
DR InterPro; IPR021619; Inhibitor_Mig-6.
DR Pfam; PF09027; GTPase_binding; 1.
DR Pfam; PF11555; Inhibitor_Mig-6; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell membrane; Complete proteome;
KW Cytoplasm; Membrane; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Tumor suppressor.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 462 ERBB receptor feedback inhibitor 1.
FT /FTId=PRO_0000096487.
FT REGION 334 363 Interaction with EGFR and ERBB2 and
FT regulation of EGFR activation.
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 131 131 Phosphothreonine (By similarity).
FT MOD_RES 251 251 Phosphoserine.
FT MOD_RES 273 273 Phosphoserine (By similarity).
FT MOD_RES 302 302 Phosphoserine (By similarity).
FT MOD_RES 461 461 Phosphoserine.
FT VARIANT 109 109 D -> N (in dbSNP:rs34781518).
FT /FTId=VAR_063039.
FT VARIANT 158 158 I -> L (in dbSNP:rs34974993).
FT /FTId=VAR_050975.
FT MUTAGEN 346 346 M->A: Abolishes inhibition of EGFR
FT activity.
FT MUTAGEN 352 352 F->A: Abolishes inhibition of EGFR
FT activity.
FT MUTAGEN 358 358 Y->A: Abolishes inhibition of EGFR
FT activity.
FT CONFLICT 7 7 A -> T (in Ref. 1).
FT CONFLICT 36 36 S -> C (in Ref. 1).
FT HELIX 342 344
FT TURN 356 358
SQ SEQUENCE 462 AA; 50560 MW; 7AFA9F6CEB602912 CRC64;
MSIAGVAAQE IRVPLKTGFL HNGRAMGNMR KTYWSSRSEF KNNFLNIDPI TMAYSLNSSA
QERLIPLGHA SKSAPMNGHC FAENGPSQKS SLPPLLIPPS ENLGPHEEDQ VVCGFKKLTV
NGVCASTPPL TPIKNSPSLF PCAPLCERGS RPLPPLPISE ALSLDDTDCE VEFLTSSDTD
FLLEDSTLSD FKYDVPGRRS FRGCGQINYA YFDTPAVSAA DLSYVSDQNG GVPDPNPPPP
QTHRRLRRSH SGPAGSFNKP AIRISNCCIH RASPNSDEDK PEVPPRVPIP PRPVKPDYRR
WSAEVTSSTY SDEDRPPKVP PREPLSPSNS RTPSPKSLPS YLNGVMPPTQ SFAPDPKYVS
SKALQRQNSE GSASKVPCIL PIIENGKKVS STHYYLLPER PPYLDKYEKF FREAEETNGG
AQIQPLPADC GISSATEKPD SKTKMDLGGH VKRKHLSYVV SP
//
ID ERRFI_HUMAN Reviewed; 462 AA.
AC Q9UJM3; B2RDX9; Q9NTG9; Q9UD05;
DT 27-JAN-2003, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-2000, sequence version 1.
DT 22-JAN-2014, entry version 101.
DE RecName: Full=ERBB receptor feedback inhibitor 1;
DE AltName: Full=Mitogen-inducible gene 6 protein;
DE Short=MIG-6;
GN Name=ERRFI1; Synonyms=MIG6;
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], AND SUBCELLULAR LOCATION.
RX PubMed=7641805; DOI=10.1006/excr.1995.1261;
RA Wick M., Buerger C., Funk M., Mueller R.;
RT "Identification of a novel mitogen-inducible gene (mig-6): regulation
RT during G1 progression and differentiation.";
RL Exp. Cell Res. 219:527-535(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Van Laar T., Schouten T., van der Eb A.J., Terleth C.;
RT "The gene for Mig-6 is regulated by methylmethanesulphonate and shows
RT high expression in the liver.";
RL Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 302-462.
RC TISSUE=Testis;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-461, 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 [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-251 AND SER-461, AND
RP MASS 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 [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-251 AND SER-461, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT SER-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
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 [12]
RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS) OF 325-364 IN COMPLEX WITH EGFR,
RP SUBUNIT, MUTAGENESIS OF MET-346; PHE-352 AND TYR-358, AND DOMAIN.
RX PubMed=18046415; DOI=10.1038/nature05998;
RA Zhang X., Pickin K.A., Bose R., Jura N., Cole P.A., Kuriyan J.;
RT "Inhibition of the EGF receptor by binding of MIG6 to an activating
RT kinase domain interface.";
RL Nature 450:741-744(2007).
CC -!- FUNCTION: Negative regulator of EGFR signaling in skin
CC morphogenesis. Acts as a negative regulator for several EGFR
CC family members, including ERBB2, ERBB3 and ERBB4. Inhibits EGFR
CC catalytic activity by interfering with its dimerization. Inhibits
CC autophosphorylation of EGFR, ERBB2 and ERBB4. Important for normal
CC keratinocyte proliferation and differentiation. Plays a role in
CC modulating the response to steroid hormones in the uterus.
CC Required for normal response to progesterone in the uterus and for
CC fertility. Mediates epithelial estrogen responses in the uterus by
CC regulating ESR1 levels and activation. Important for regulation of
CC endometrium cell proliferation. Important for normal prenatal and
CC perinatal lung development (By similarity).
CC -!- SUBUNIT: Interacts with ERBB2 (By similarity). Interacts with
CC EGFR.
CC -!- INTERACTION:
CC O14757:CHEK1; NbExp=2; IntAct=EBI-2941912, EBI-974488;
CC P00533:EGFR; NbExp=8; IntAct=EBI-2941912, EBI-297353;
CC P62993:GRB2; NbExp=8; IntAct=EBI-2941912, EBI-401755;
CC P31947:SFN; NbExp=3; IntAct=EBI-2941912, EBI-476295;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane; Peripheral
CC membrane protein; Cytoplasmic side (By similarity). Nucleus (By
CC similarity). Note=Associated with the plasma membrane of basal
CC skin keratinocytes. Translocates into the nucleus of
CC differentiating suprabasal keratinocytes (By similarity).
CC -!- INDUCTION: Levels are very low in quiescent cells. Up-regulated by
CC mitogens.
CC -!- DOMAIN: The EGFR-binding region prevents binding of a cyclin-like
CC activator to the EGFR kinase domain, and thereby keeps EGFR in an
CC inactive conformation. Also maintains EGFR in an inactive
CC conformation by preventing formation of an asymmetric homodimer.
CC -!- SIMILARITY: Belongs to the MIG6 family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/ERRFI1ID44147ch1p36.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AJ276373; CAC20426.1; -; mRNA.
DR EMBL; AL034417; CAB52551.1; -; Genomic_DNA.
DR EMBL; AK315718; BAG38076.1; -; mRNA.
DR EMBL; CH471130; EAW71593.1; -; Genomic_DNA.
DR EMBL; BC025337; AAH25337.1; -; mRNA.
DR EMBL; AL137274; CAB70672.1; -; mRNA.
DR PIR; T46346; T46346.
DR RefSeq; NP_061821.1; NM_018948.3.
DR UniGene; Hs.605445; -.
DR PDB; 2RF9; X-ray; 3.50 A; C/D=315-374.
DR PDB; 2RFD; X-ray; 3.60 A; C/D=340-364.
DR PDB; 2RFE; X-ray; 2.90 A; E/F=325-364.
DR PDB; 4I21; X-ray; 3.37 A; C/D=315-374.
DR PDBsum; 2RF9; -.
DR PDBsum; 2RFD; -.
DR PDBsum; 2RFE; -.
DR PDBsum; 4I21; -.
DR ProteinModelPortal; Q9UJM3; -.
DR SMR; Q9UJM3; 335-364.
DR DIP; DIP-42379N; -.
DR IntAct; Q9UJM3; 18.
DR MINT; MINT-1591605; -.
DR STRING; 9606.ENSP00000366702; -.
DR PhosphoSite; Q9UJM3; -.
DR DMDM; 27923810; -.
DR PaxDb; Q9UJM3; -.
DR PRIDE; Q9UJM3; -.
DR DNASU; 54206; -.
DR Ensembl; ENST00000377482; ENSP00000366702; ENSG00000116285.
DR GeneID; 54206; -.
DR KEGG; hsa:54206; -.
DR UCSC; uc001aoz.3; human.
DR CTD; 54206; -.
DR GeneCards; GC01M008064; -.
DR HGNC; HGNC:18185; ERRFI1.
DR HPA; HPA027206; -.
DR MIM; 608069; gene.
DR neXtProt; NX_Q9UJM3; -.
DR PharmGKB; PA142671904; -.
DR eggNOG; NOG147618; -.
DR HOGENOM; HOG000234207; -.
DR HOVERGEN; HBG031710; -.
DR InParanoid; Q9UJM3; -.
DR OMA; KPAIRIS; -.
DR PhylomeDB; Q9UJM3; -.
DR SignaLink; Q9UJM3; -.
DR ChiTaRS; ERRFI1; human.
DR EvolutionaryTrace; Q9UJM3; -.
DR GeneWiki; ERRFI1; -.
DR GenomeRNAi; 54206; -.
DR NextBio; 56530; -.
DR PRO; PR:Q9UJM3; -.
DR ArrayExpress; Q9UJM3; -.
DR Bgee; Q9UJM3; -.
DR CleanEx; HS_ERRFI1; -.
DR Genevestigator; Q9UJM3; -.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0031234; C:extrinsic to cytoplasmic side of plasma membrane; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005100; F:Rho GTPase activator activity; TAS:ProtInc.
DR GO; GO:0048286; P:lung alveolus development; ISS:UniProtKB.
DR GO; GO:0060428; P:lung epithelium development; ISS:UniProtKB.
DR GO; GO:0060426; P:lung vasculature development; ISS:UniProtKB.
DR GO; GO:0007175; P:negative regulation of epidermal growth factor-activated receptor activity; IDA:UniProtKB.
DR GO; GO:0031953; P:negative regulation of protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0045616; P:regulation of keratinocyte differentiation; ISS:UniProtKB.
DR GO; GO:0006950; P:response to stress; TAS:ProtInc.
DR GO; GO:0043589; P:skin morphogenesis; ISS:UniProtKB.
DR InterPro; IPR015116; Cdc42_binding_dom_like.
DR InterPro; IPR021619; Inhibitor_Mig-6.
DR Pfam; PF09027; GTPase_binding; 1.
DR Pfam; PF11555; Inhibitor_Mig-6; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cell membrane; Complete proteome;
KW Cytoplasm; Membrane; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; Tumor suppressor.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 462 ERBB receptor feedback inhibitor 1.
FT /FTId=PRO_0000096487.
FT REGION 334 363 Interaction with EGFR and ERBB2 and
FT regulation of EGFR activation.
FT MOD_RES 2 2 N-acetylserine.
FT MOD_RES 131 131 Phosphothreonine (By similarity).
FT MOD_RES 251 251 Phosphoserine.
FT MOD_RES 273 273 Phosphoserine (By similarity).
FT MOD_RES 302 302 Phosphoserine (By similarity).
FT MOD_RES 461 461 Phosphoserine.
FT VARIANT 109 109 D -> N (in dbSNP:rs34781518).
FT /FTId=VAR_063039.
FT VARIANT 158 158 I -> L (in dbSNP:rs34974993).
FT /FTId=VAR_050975.
FT MUTAGEN 346 346 M->A: Abolishes inhibition of EGFR
FT activity.
FT MUTAGEN 352 352 F->A: Abolishes inhibition of EGFR
FT activity.
FT MUTAGEN 358 358 Y->A: Abolishes inhibition of EGFR
FT activity.
FT CONFLICT 7 7 A -> T (in Ref. 1).
FT CONFLICT 36 36 S -> C (in Ref. 1).
FT HELIX 342 344
FT TURN 356 358
SQ SEQUENCE 462 AA; 50560 MW; 7AFA9F6CEB602912 CRC64;
MSIAGVAAQE IRVPLKTGFL HNGRAMGNMR KTYWSSRSEF KNNFLNIDPI TMAYSLNSSA
QERLIPLGHA SKSAPMNGHC FAENGPSQKS SLPPLLIPPS ENLGPHEEDQ VVCGFKKLTV
NGVCASTPPL TPIKNSPSLF PCAPLCERGS RPLPPLPISE ALSLDDTDCE VEFLTSSDTD
FLLEDSTLSD FKYDVPGRRS FRGCGQINYA YFDTPAVSAA DLSYVSDQNG GVPDPNPPPP
QTHRRLRRSH SGPAGSFNKP AIRISNCCIH RASPNSDEDK PEVPPRVPIP PRPVKPDYRR
WSAEVTSSTY SDEDRPPKVP PREPLSPSNS RTPSPKSLPS YLNGVMPPTQ SFAPDPKYVS
SKALQRQNSE GSASKVPCIL PIIENGKKVS STHYYLLPER PPYLDKYEKF FREAEETNGG
AQIQPLPADC GISSATEKPD SKTKMDLGGH VKRKHLSYVV SP
//
MIM
608069
*RECORD*
*FIELD* NO
608069
*FIELD* TI
*608069 ERBB RECEPTOR FEEDBACK INHIBITOR 1; ERRFI1
;;MITOGEN-INDUCIBLE GENE 6; MIG6;;
read moreRECEPTOR-ASSOCIATED LATE TRANSDUCER; RALT;;
GENE 33, RAT, HOMOLOG OF
*FIELD* TX
DESCRIPTION
ERRFI1 is a cytoplasmic protein whose expression is upregulated with
cell growth (Wick et al., 1995). It shares significant homology with the
protein product of rat gene-33, which is induced during cell stress and
mediates cell signaling (Makkinje et al., 2000; Fiorentino et al.,
2000).
CLONING
By differential screening of cDNA libraries developed from unstimulated
versus serum-stimulated lung fibroblasts, followed by 5-prime RACE of a
hepatoma cell cDNA library, Wick et al. (1995) cloned ERRFI1, which they
called MIG6. The deduced protein contains 462 amino acids and shares
significant homology with the rat gene-33 protein product.
Epitope-tagged MIG6 showed exclusively cytoplasmic staining following
transfection into mouse fibroblasts.
Makkinje et al. (2000) determined that the protein encoded by rat
gene-33 contains a CRIB domain, an SH3-binding motif, a 14-3-3 (see
113508)-binding domain, an ACK (606994) homology domain, and a
PDZ-binding region. Makkinje et al. (2000) hypothesized that the protein
is an adaptor capable of binding monomeric GTPases of the Rho (see
602924) subfamily.
GENE FUNCTION
Wick et al. (1995) determined that serum induction of the MIG6
transcript was blocked by inhibition of RNA polymerase and was partially
blocked by inhibitors of protein synthesis. In contrast to other
mitogen-responsive genes, MIG6 mRNA expression was also regulated during
normal cell cycle progression, showing a clear peak around mid-G1.
Consistent with cell cycle regulation, terminal differentiation of
myeloid leukemia cells to either granulocytic or macrophage-like cells
led to clear changes in MIG6 mRNA levels. The pattern of MIG6 expression
depended upon the lineage induced.
Makkinje et al. (2000) determined that gene-33 mRNA was induced in rat
renal mesangial cells following osmotic stress, exposure to human
endothelin-1 (131240) or angiotensin-2 (106150), or calcium
mobilization. It was also induced in human pulmonary epithelial cells
following mechanical strain. Gene-33 protein interacted in vivo with
CDC42 (116952); in vitro, this interaction was GTP-dependent. Transient
expression of gene-33 in human embryonic kidney cells resulted in
selective activation of stress-activated protein kinases (see MAPK8;
601158).
Fiorentino et al. (2000) showed that the rat gene-33 protein, which they
designated Ralt, interacted with Erbb2 (164870). Direct interaction
required the catalytic activity of Erbb2. Expression of gene-33 was
absent in quiescent mouse fibroblasts but was induced following serum
stimulation. Overexpression of gene-33 in mouse fibroblasts inhibited
several Erbb2-dependent processes, including cell proliferation, cell
transformation, and the sustained activation of Erk1 (601795) and Erk2
(176948). Overexpression did not inhibit cell proliferation or ERK
activation induced by serum, and it did not inhibit cell transformation
induced by Ras (190020) or Src (190090). Fiorentino et al. (2000)
hypothesized that gene-33 is a feedback inhibitor of Erbb2 and
suppresses its mitogenic and oncogenic activity.
By Western blot analysis, Ferby et al. (2006) found undetectable MIG6
levels in 6 of 9 human breast cancer cell lines expressing EGFR
(131550). Of those, 3 cell lines showed the highest levels of EGFR
phosphorylation. In contrast, the 3 cell lines expressing MIG6 had low
to undetectable phosphorylation of EGFR. Depletion of MIG6 by siRNA
resulted in increased phosphorylation of EGFR over time as MIG6 protein
levels decreased. Ferby et al. (2006) concluded that downregulation of
MIG6 leads to activation of ERBB signaling.
BIOCHEMICAL FEATURES
- Crystal Structure
Zhang et al. (2007) determined the crystal structure of a complex
between the EGFR kinase domain and a fragment of MIG6 at 2.9-angstrom
resolution, which showed that an approximately 25-residue epitope from
MIG6 binds to the distal surface of the C lobe of the kinase domain.
Biochemical and cell-based analyses confirmed that this interaction
contributes to EGFR inhibition by blocking the formation of the
activating dimer interface. A longer MIG6 peptide that is extended C
terminal to segment 1 has increased potency as an inhibitor of the
activated EGFR kinase domain, while retaining a critical dependence on
segment 1. Zhang et al. (2007) showed that signaling by EGFR molecules
that contain constitutively active kinase domains still requires
formation of the asymmetric dimer, underscoring the importance of dimer
interface blockage in MIG6-mediated inhibition.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the ERRFI1
gene to chromosome 1 (TMAP stSG4733).
ANIMAL MODEL
Zhang et al. (2005) found that Mig6 -/- mice were viable, but they were
born in less than the expected ratio, indicating some embryonic
lethality. Although Mig6 was highly expressed in wildtype mouse liver
and kidney, no obvious pathologic changes were observed in these tissues
in Mig6 -/- mice. Instead, most Mig6 -/- mice showed an abnormal gait at
1 month of age. With time, they showed progressive enlargement and
deformity of multiple joints, including bony outgrowths or osteophyte
formation within joint spaces, especially the knees, ankles, and
temporomandibular joints (TMJs). All Mig6 -/- mice developed joint
deformities, and the majority died within 6 months, most likely due to
TMJ ankylosis, resulting in the inability to eat or drink. The
osteophyte formation appeared to be due to proliferation of mesenchymal
progenitor cells, followed by differentiation into chondrocytes.
Ferby et al. (2006) found that Errfi1 -/- mice were born at the expected
mendelian ratio and, within a few days after birth, they showed a fully
penetrant skin phenotype characterized by thickening, flaking, and
ulceration of tail and footpad skin. The epidermal hyperplasia varied
somewhat in severity, depending on genetic background. Most Errfi1 -/-
mice also had a 5- to 10-day delay in the opening of the eyelids
compared with control littermates. Deletion of the Errfi1 gene caused
hyperactivation of endogenous Egfr and sustained signaling through the
MAPK (see MAPK1; 176948) pathway, resulting in overproliferation and
impaired differentiation of epidermal keratinocytes. Ferby et al. (2006)
showed that Errfi1 -/- mice developed spontaneous tumors in various
organs and were highly susceptible to chemically induced skin tumors.
*FIELD* RF
1. Ferby, I.; Reschke, M.; Kudlacek, O.; Knyazev, P.; Pante, G.; Amann,
K.; Sommergruber, W.; Kraut, N.; Ullrich, A.; Fassler, R.; Klein,
R.: Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis
and tumor formation. Nature Med. 12: 568-573, 2006. Note: Erratum:
Nature Med. 12: 862 only, 2006.
2. Fiorentino, L.; Pertica, C.; Fiorini, M.; Talora, C.; Crescenzi,
M.; Catellani, L.; Alema, S.; Benedetti, P.; Segatto, O.: Inhibition
of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced
signal transducer which binds to the ErbB-2 kinase domain. Molec.
Cell. Biol. 20: 7735-7750, 2000.
3. Makkinje, A.; Quinn, D. A.; Chen, A.; Cadilla, C. L.; Force, T.;
Bonventre, J. V.; Kyriakis, J. M.: Gene 33/Mig-6, a transcriptionally
inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK:
a potential marker transcript for chronic pathologic conditions, such
as diabetic nephropathy. Possible role in the response to persistent
stress. J. Biol. Chem. 275: 17838-17847, 2000.
4. Wick, M.; Burger, C.; Funk, M.; Muller, R.: Identification of
a novel mitogen-inducible gene (mig-6): regulation during G1 progression
and differentiation. Exp. Cell Res. 219: 527-535, 1995.
5. Zhang, X.; Pickin, K. A.; Bose, R.; Jura, N.; Cole, P. A.; Kuriyan,
J.: Inhibition of the EGF receptor by binding of MIG6 to an activating
kinase domain interface. Nature 450: 741-744, 2007.
6. Zhang, Y.-W.; Su, Y.; Lanning, N.; Swiatek, P. J.; Bronson, R.
T.; Sigler, R.; Martin, R. W.; Vande Woude, G. F.: Targeted disruption
of Mig-6 in the mouse genome leads to early onset degenerative joint
disease. Proc. Nat. Acad. Sci. 102: 11740-11745, 2005.
*FIELD* CN
Ada Hamosh - updated: 1/22/2008
Patricia A. Hartz - updated: 11/1/2006
Patricia A. Hartz - updated: 9/13/2006
*FIELD* CD
Patricia A. Hartz: 9/2/2003
*FIELD* ED
terry: 12/20/2012
alopez: 1/24/2008
terry: 1/22/2008
mgross: 11/3/2006
terry: 11/1/2006
wwang: 9/18/2006
terry: 9/13/2006
mgross: 9/2/2003
*RECORD*
*FIELD* NO
608069
*FIELD* TI
*608069 ERBB RECEPTOR FEEDBACK INHIBITOR 1; ERRFI1
;;MITOGEN-INDUCIBLE GENE 6; MIG6;;
read moreRECEPTOR-ASSOCIATED LATE TRANSDUCER; RALT;;
GENE 33, RAT, HOMOLOG OF
*FIELD* TX
DESCRIPTION
ERRFI1 is a cytoplasmic protein whose expression is upregulated with
cell growth (Wick et al., 1995). It shares significant homology with the
protein product of rat gene-33, which is induced during cell stress and
mediates cell signaling (Makkinje et al., 2000; Fiorentino et al.,
2000).
CLONING
By differential screening of cDNA libraries developed from unstimulated
versus serum-stimulated lung fibroblasts, followed by 5-prime RACE of a
hepatoma cell cDNA library, Wick et al. (1995) cloned ERRFI1, which they
called MIG6. The deduced protein contains 462 amino acids and shares
significant homology with the rat gene-33 protein product.
Epitope-tagged MIG6 showed exclusively cytoplasmic staining following
transfection into mouse fibroblasts.
Makkinje et al. (2000) determined that the protein encoded by rat
gene-33 contains a CRIB domain, an SH3-binding motif, a 14-3-3 (see
113508)-binding domain, an ACK (606994) homology domain, and a
PDZ-binding region. Makkinje et al. (2000) hypothesized that the protein
is an adaptor capable of binding monomeric GTPases of the Rho (see
602924) subfamily.
GENE FUNCTION
Wick et al. (1995) determined that serum induction of the MIG6
transcript was blocked by inhibition of RNA polymerase and was partially
blocked by inhibitors of protein synthesis. In contrast to other
mitogen-responsive genes, MIG6 mRNA expression was also regulated during
normal cell cycle progression, showing a clear peak around mid-G1.
Consistent with cell cycle regulation, terminal differentiation of
myeloid leukemia cells to either granulocytic or macrophage-like cells
led to clear changes in MIG6 mRNA levels. The pattern of MIG6 expression
depended upon the lineage induced.
Makkinje et al. (2000) determined that gene-33 mRNA was induced in rat
renal mesangial cells following osmotic stress, exposure to human
endothelin-1 (131240) or angiotensin-2 (106150), or calcium
mobilization. It was also induced in human pulmonary epithelial cells
following mechanical strain. Gene-33 protein interacted in vivo with
CDC42 (116952); in vitro, this interaction was GTP-dependent. Transient
expression of gene-33 in human embryonic kidney cells resulted in
selective activation of stress-activated protein kinases (see MAPK8;
601158).
Fiorentino et al. (2000) showed that the rat gene-33 protein, which they
designated Ralt, interacted with Erbb2 (164870). Direct interaction
required the catalytic activity of Erbb2. Expression of gene-33 was
absent in quiescent mouse fibroblasts but was induced following serum
stimulation. Overexpression of gene-33 in mouse fibroblasts inhibited
several Erbb2-dependent processes, including cell proliferation, cell
transformation, and the sustained activation of Erk1 (601795) and Erk2
(176948). Overexpression did not inhibit cell proliferation or ERK
activation induced by serum, and it did not inhibit cell transformation
induced by Ras (190020) or Src (190090). Fiorentino et al. (2000)
hypothesized that gene-33 is a feedback inhibitor of Erbb2 and
suppresses its mitogenic and oncogenic activity.
By Western blot analysis, Ferby et al. (2006) found undetectable MIG6
levels in 6 of 9 human breast cancer cell lines expressing EGFR
(131550). Of those, 3 cell lines showed the highest levels of EGFR
phosphorylation. In contrast, the 3 cell lines expressing MIG6 had low
to undetectable phosphorylation of EGFR. Depletion of MIG6 by siRNA
resulted in increased phosphorylation of EGFR over time as MIG6 protein
levels decreased. Ferby et al. (2006) concluded that downregulation of
MIG6 leads to activation of ERBB signaling.
BIOCHEMICAL FEATURES
- Crystal Structure
Zhang et al. (2007) determined the crystal structure of a complex
between the EGFR kinase domain and a fragment of MIG6 at 2.9-angstrom
resolution, which showed that an approximately 25-residue epitope from
MIG6 binds to the distal surface of the C lobe of the kinase domain.
Biochemical and cell-based analyses confirmed that this interaction
contributes to EGFR inhibition by blocking the formation of the
activating dimer interface. A longer MIG6 peptide that is extended C
terminal to segment 1 has increased potency as an inhibitor of the
activated EGFR kinase domain, while retaining a critical dependence on
segment 1. Zhang et al. (2007) showed that signaling by EGFR molecules
that contain constitutively active kinase domains still requires
formation of the asymmetric dimer, underscoring the importance of dimer
interface blockage in MIG6-mediated inhibition.
MAPPING
The International Radiation Hybrid Mapping Consortium mapped the ERRFI1
gene to chromosome 1 (TMAP stSG4733).
ANIMAL MODEL
Zhang et al. (2005) found that Mig6 -/- mice were viable, but they were
born in less than the expected ratio, indicating some embryonic
lethality. Although Mig6 was highly expressed in wildtype mouse liver
and kidney, no obvious pathologic changes were observed in these tissues
in Mig6 -/- mice. Instead, most Mig6 -/- mice showed an abnormal gait at
1 month of age. With time, they showed progressive enlargement and
deformity of multiple joints, including bony outgrowths or osteophyte
formation within joint spaces, especially the knees, ankles, and
temporomandibular joints (TMJs). All Mig6 -/- mice developed joint
deformities, and the majority died within 6 months, most likely due to
TMJ ankylosis, resulting in the inability to eat or drink. The
osteophyte formation appeared to be due to proliferation of mesenchymal
progenitor cells, followed by differentiation into chondrocytes.
Ferby et al. (2006) found that Errfi1 -/- mice were born at the expected
mendelian ratio and, within a few days after birth, they showed a fully
penetrant skin phenotype characterized by thickening, flaking, and
ulceration of tail and footpad skin. The epidermal hyperplasia varied
somewhat in severity, depending on genetic background. Most Errfi1 -/-
mice also had a 5- to 10-day delay in the opening of the eyelids
compared with control littermates. Deletion of the Errfi1 gene caused
hyperactivation of endogenous Egfr and sustained signaling through the
MAPK (see MAPK1; 176948) pathway, resulting in overproliferation and
impaired differentiation of epidermal keratinocytes. Ferby et al. (2006)
showed that Errfi1 -/- mice developed spontaneous tumors in various
organs and were highly susceptible to chemically induced skin tumors.
*FIELD* RF
1. Ferby, I.; Reschke, M.; Kudlacek, O.; Knyazev, P.; Pante, G.; Amann,
K.; Sommergruber, W.; Kraut, N.; Ullrich, A.; Fassler, R.; Klein,
R.: Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis
and tumor formation. Nature Med. 12: 568-573, 2006. Note: Erratum:
Nature Med. 12: 862 only, 2006.
2. Fiorentino, L.; Pertica, C.; Fiorini, M.; Talora, C.; Crescenzi,
M.; Catellani, L.; Alema, S.; Benedetti, P.; Segatto, O.: Inhibition
of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced
signal transducer which binds to the ErbB-2 kinase domain. Molec.
Cell. Biol. 20: 7735-7750, 2000.
3. Makkinje, A.; Quinn, D. A.; Chen, A.; Cadilla, C. L.; Force, T.;
Bonventre, J. V.; Kyriakis, J. M.: Gene 33/Mig-6, a transcriptionally
inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK:
a potential marker transcript for chronic pathologic conditions, such
as diabetic nephropathy. Possible role in the response to persistent
stress. J. Biol. Chem. 275: 17838-17847, 2000.
4. Wick, M.; Burger, C.; Funk, M.; Muller, R.: Identification of
a novel mitogen-inducible gene (mig-6): regulation during G1 progression
and differentiation. Exp. Cell Res. 219: 527-535, 1995.
5. Zhang, X.; Pickin, K. A.; Bose, R.; Jura, N.; Cole, P. A.; Kuriyan,
J.: Inhibition of the EGF receptor by binding of MIG6 to an activating
kinase domain interface. Nature 450: 741-744, 2007.
6. Zhang, Y.-W.; Su, Y.; Lanning, N.; Swiatek, P. J.; Bronson, R.
T.; Sigler, R.; Martin, R. W.; Vande Woude, G. F.: Targeted disruption
of Mig-6 in the mouse genome leads to early onset degenerative joint
disease. Proc. Nat. Acad. Sci. 102: 11740-11745, 2005.
*FIELD* CN
Ada Hamosh - updated: 1/22/2008
Patricia A. Hartz - updated: 11/1/2006
Patricia A. Hartz - updated: 9/13/2006
*FIELD* CD
Patricia A. Hartz: 9/2/2003
*FIELD* ED
terry: 12/20/2012
alopez: 1/24/2008
terry: 1/22/2008
mgross: 11/3/2006
terry: 11/1/2006
wwang: 9/18/2006
terry: 9/13/2006
mgross: 9/2/2003