ERBB2_MESAU
ID ERBB2_MESAU Reviewed; 1254 AA.
AC Q60553;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 160.
DE RecName: Full=Receptor tyrosine-protein kinase erbB-2;
DE EC=2.7.10.1;
DE AltName: Full=Proto-oncogene Neu;
DE AltName: Full=Proto-oncogene c-ErbB-2;
DE AltName: Full=p185erbB2;
DE AltName: CD_antigen=CD340;
DE Flags: Precursor;
GN Name=ERBB2; Synonyms=NEU;
OS Mesocricetus auratus (Golden hamster).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Mesocricetus.
OX NCBI_TaxID=10036;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS ONCOGENIC GLU-658 AND GLU-659.
RC TISSUE=Nerve;
RX PubMed=7908275; DOI=10.1016/0378-1119(94)90553-3;
RA Nakamura T., Ushijima T., Ishizaka Y., Nagao M., Arai M., Yamazaki Y.,
RA Ishikawa T.;
RT "Cloning and activation of the Syrian hamster neu proto-oncogene.";
RL Gene 140:251-255(1994).
CC -!- FUNCTION: Protein tyrosine kinase that is part of several cell surface
CC receptor complexes, but that apparently needs a coreceptor for ligand
CC binding. Essential component of a neuregulin-receptor complex, although
CC neuregulins do not interact with it alone. GP30 is a potential ligand
CC for this receptor. Regulates outgrowth and stabilization of peripheral
CC microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1
CC signaling pathway elicits the phosphorylation and thus the inhibition
CC of GSK3B at cell membrane. This prevents the phosphorylation of APC and
CC CLASP2, allowing its association with the cell membrane. In turn,
CC membrane-bound APC allows the localization of MACF1 to the cell
CC membrane, which is required for microtubule capture and stabilization
CC (By similarity). {ECO:0000250}.
CC -!- FUNCTION: In the nucleus is involved in transcriptional regulation.
CC Associates with the 5'-TCAAATTC-3' sequence in the PTGS2/COX-2 promoter
CC and activates its transcription. Implicated in transcriptional
CC activation of CDKN1A; the function involves STAT3 and SRC. Involved in
CC the transcription of rRNA genes by RNA Pol I and enhances protein
CC synthesis and cell growth (By similarity). {ECO:0000250}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- SUBUNIT: Homodimer. Heterodimer with EGFR, ERBB3 and ERBB4. Part of a
CC complex with EGFR and either PIK3C2A or PIK3C2B. May interact with
CC PIK3C2B when phosphorylated on Tyr-1196. Interacts with PRKCABP and
CC PLXNB1. Interacts (when phosphorylated on Tyr-1247) with MEMO.
CC Interacts with MUC1. Interacts (when phosphorylated on Tyr-1139) with
CC GRB7 (via SH2 domain). Interacts (when phosphorylated on Tyr-1247) with
CC ERBIN. Interacts with SRC, KPNB1, RANBP2, EEA1, CRM1, CLTC, PTK6,
CC RPA194, MYOC and ACTB. Interacts (preferentially with the tyrosine
CC phosphorylated form) with CPNE3; this interaction occurs at the cell
CC membrane and is increased in a growth factor heregulin-dependent
CC manner. Interacts with HSP90AA1 and HSP90AB1 in an ATP-dependent
CC manner; the interaction suppresses ERBB2 kinase activity (By
CC similarity). Interacts with SORL1; this interaction regulates ERBB2
CC subcellular distribution by promoting its recycling after
CC internalization from endosomes back to the plasma membrane, hence
CC stimulates ERBB2-mediated signaling (By similarity).
CC {ECO:0000250|UniProtKB:P04626, ECO:0000250|UniProtKB:P70424}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P04626};
CC Single-pass type I membrane protein {ECO:0000250|UniProtKB:P04626}.
CC Early endosome {ECO:0000250|UniProtKB:P04626}. Cytoplasm, perinuclear
CC region {ECO:0000250|UniProtKB:P04626}. Nucleus
CC {ECO:0000250|UniProtKB:P04626}. Note=Translocation to the nucleus
CC requires endocytosis, probably endosomal sorting and is mediated by
CC importin beta-1/KPNB1. Also detected in endosome-to-TGN retrograde
CC vesicles. {ECO:0000250|UniProtKB:P04626}.
CC -!- PTM: Autophosphorylated. Autophosphorylation occurs in trans, i.e. one
CC subunit of the dimeric receptor phosphorylates tyrosine residues on the
CC other subunit. Ligand-binding increases phosphorylation on tyrosine
CC residues. Signaling via SEMA4C promotes phosphorylation at Tyr-1247.
CC Dephosphorylated by PTPN12. {ECO:0000250|UniProtKB:P04626}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. EGF receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; D16295; BAA03801.1; -; mRNA.
DR PIR; I48161; I48161.
DR RefSeq; NP_001268310.1; NM_001281381.1.
DR AlphaFoldDB; Q60553; -.
DR SMR; Q60553; -.
DR STRING; 10036.XP_005076089.1; -.
DR PRIDE; Q60553; -.
DR GeneID; 101822760; -.
DR CTD; 2064; -.
DR eggNOG; KOG1025; Eukaryota.
DR OrthoDB; 81952at2759; -.
DR BRENDA; 2.7.10.1; 3239.
DR Proteomes; UP000189706; Unplaced.
DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0098590; C:plasma membrane region; IEA:UniProt.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0001042; F:RNA polymerase I core binding; ISS:UniProtKB.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IEA:UniProtKB-EC.
DR GO; GO:0048513; P:animal organ development; IEA:UniProt.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; ISS:UniProtKB.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; ISS:UniProtKB.
DR GO; GO:0007417; P:central nervous system development; IEA:UniProt.
DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB.
DR GO; GO:0030307; P:positive regulation of cell growth; ISS:UniProtKB.
DR GO; GO:0090314; P:positive regulation of protein targeting to membrane; ISS:UniProtKB.
DR GO; GO:0045943; P:positive regulation of transcription by RNA polymerase I; ISS:UniProtKB.
DR GO; GO:0045727; P:positive regulation of translation; ISS:UniProtKB.
DR GO; GO:0042127; P:regulation of cell population proliferation; IEA:UniProt.
DR GO; GO:0070372; P:regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0032886; P:regulation of microtubule-based process; ISS:UniProtKB.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IEA:InterPro.
DR CDD; cd00064; FU; 3.
DR Gene3D; 3.80.20.20; -; 2.
DR InterPro; IPR006211; Furin-like_Cys-rich_dom.
DR InterPro; IPR006212; Furin_repeat.
DR InterPro; IPR032778; GF_recep_IV.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR000494; Rcpt_L-dom.
DR InterPro; IPR036941; Rcpt_L-dom_sf.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016245; Tyr_kinase_EGF/ERB/XmrK_rcpt.
DR Pfam; PF00757; Furin-like; 1.
DR Pfam; PF14843; GF_recep_IV; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF01030; Recep_L_domain; 2.
DR PIRSF; PIRSF000619; TyrPK_EGF-R; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00261; FU; 4.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF57184; SSF57184; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PE 2: Evidence at transcript level;
KW Activator; ATP-binding; Cell membrane; Cytoplasm; Disulfide bond; Endosome;
KW Glycoprotein; Kinase; Membrane; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Proto-oncogene; Receptor; Reference proteome; Signal;
KW Transcription; Transcription regulation; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase.
FT SIGNAL 1..22
FT /evidence="ECO:0000255"
FT CHAIN 23..1254
FT /note="Receptor tyrosine-protein kinase erbB-2"
FT /id="PRO_0000016670"
FT TOPO_DOM 23..652
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 653..675
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 676..1254
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 720..987
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 676..689
FT /note="Required for interaction with KPNB1 and EEA1"
FT /evidence="ECO:0000250"
FT REGION 1029..1116
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1133..1179
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1195..1197
FT /note="Interaction with PIK3C2B"
FT /evidence="ECO:0000250"
FT REGION 1223..1254
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 676..689
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000250"
FT COMPBIAS 1142..1160
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 845
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 726..734
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 753
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 1054
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT MOD_RES 1078
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P06494"
FT MOD_RES 1083
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT MOD_RES 1107
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT MOD_RES 1112
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT MOD_RES 1139
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT MOD_RES 1166
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT MOD_RES 1196
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT MOD_RES 1247
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT CARBOHYD 68
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 125
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 187
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 259
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 530
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 571
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 629
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 26..53
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 162..192
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 195..204
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 199..212
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 236..244
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 240..252
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 255..264
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 268..295
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 299..311
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 315..331
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 334..338
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 342..367
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 475..504
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 511..520
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 515..528
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 531..540
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 544..560
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 563..576
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 567..584
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 587..596
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 600..623
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 626..634
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT DISULFID 630..642
FT /evidence="ECO:0000250|UniProtKB:P04626"
FT VARIANT 658
FT /note="V -> E (in oncogenic NEU)"
FT /evidence="ECO:0000269|PubMed:7908275"
FT VARIANT 659
FT /note="V -> E (in oncogenic NEU)"
FT /evidence="ECO:0000269|PubMed:7908275"
SQ SEQUENCE 1254 AA; 138253 MW; 974C3791C21F2BE1 CRC64;
MELAAWCGWG LLLALLSPGA SGTQVCTGTD MKLRLPASPE THLDIVRHLY QGCQVVQGNL
ELTYLPANAT LSFLQDIQEV QGYMLIAHSQ VRHVPLQRLR IVRGTQLFED KYALAVLDNR
DPLDNVTTAT GRTPEGLREL QLRSLTEILK GGVLIRGNPQ LCYQDTVLWK DVFRKNNQLA
PVDIDTNRSR ACPPCAPACK DNHCWGASPE DCQTLTGTIA PRAVPAARAR LPTDCCHEQC
AAGCTGPKHS DCLACLHFNH SGICELHCPA LVTYNTDTFE SMPNPEGRYT FGASCVTTCP
YNYLSTEVGS CTLVCPLNNQ EVTAEDGTQR CEKCSKSCAR VCYGLGMEHL RGARAITSAN
IQEFAGCKKI FGSLAFLPES FDGNPSSGIA PLTPEQLQVF ETLEEITGYL YISAWPDSLH
DLSVFQNLRV IRGRVLHDGA YSLALQGLGI RWLGLRSLRE LGSGLVLIHR NTHLCFVHTV
PWDQLFRNPH QALLHSGNPS EEECGLKDFA CYPLCAHGHC WGPGPTQCVN CSHFLRGQEC
VKECRVWKGL PREYVNGKHC LPCHPECQPQ NSTETCTGSE ADQCTACPHY KDSPFCVARC
PSGVKPDLSY MPIWKYPDEE GMCQPCPINC THSCVDLDER GCPAEQRASP ATSIIATVVG
ILLFLVIGVV VGILIKRRRQ KIRKYTMRRL LQETELVEPL TPSGAMPNQA QMRILKETEL
RKVKVLGSGA FGTVYKGIWI PDGENVKIPV AIKVLRENTS PKANKEILDE AYVMAGLGSP
YVSRLLGICL TSTVQLVTQL MPYGCLLDHV REHRGRLGSQ DLLNWCVQIA KGMSYLEDVR
LVHRDLAARN VLVKSPNHVK ITDFGLARLL DIDETEYHAD GGKVPIKWIA LESILRRRFT
HQSDVWSYGV TVWELMTFGA KPYDGIPARE IPDLLEKGER LPQPPICTID VYMIMVKCWM
IDSECRPRFR ELVSEFSRMA RDPQRFVVIQ NEDLGPSSPL DSTFYRSLLE DDDMGDLVDA
EEYLVPQQGF FFPDPAPGAG STAHRRHRSS STRSGGGELT LGMEPSGEEP PRSPLAPSEG
AGSDVFEGEL GMGATKGPQS ISPRDLSPLQ RYSEDPTLPL PTETDGYVAP LACSPQPEYV
NQPEVRPQPP LTPEGPLPPV RPAGATLERP KTLSPGKNGV VKDVFTFGGA VENPEYLVPR
GGSASQPHPP ALCPAFDNLY YWDQDPSERG SPPNTFEGTP TAENPEYLGL DVPV
