CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-012531
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 Receptor tyrosine-protein kinase erbB-4 
Protein Synonyms/Alias
 Proto-oncogene-like protein c-ErbB-4; Tyrosine kinase-type cell surface receptor HER4; p180erbB4; ERBB4 intracellular domain; 4ICD; E4ICD; s80HER4 
Gene Name
 ERBB4 
Gene Synonyms/Alias
 HER4 
Created Date
 July 27, 2013 
Organism
 Homo sapiens (Human) 
NCBI Taxa ID
 9606 
Lysine Modification
Position
Peptide
Type
References
722ETELKRVKVLGSGAFubiquitination[1]
745VPEGETVKIPVAIKIubiquitination[1, 2]
858VKSPNHVKITDFGLAubiquitination[1]
873RLLEGDEKEYNADGGacetylation[3]
881EYNADGGKMPIKWMAacetylation[3]
1265YLQEYSTKYFYKQNGubiquitination[1, 2]
Reference
 [1] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [2] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [3] Regulation of cellular metabolism by protein lysine acetylation.
 Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H, Li Y, Shi J, An W, Hancock SM, He F, Qin L, Chin J, Yang P, Chen X, Lei Q, Xiong Y, Guan KL.
 Science. 2010 Feb 19;327(5968):1000-4. [PMID: 20167786] 
Functional Description
 Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis. 
Sequence Annotation
 DOMAIN 718 985 Protein kinase.
 NP_BIND 724 732 ATP (By similarity).
 NP_BIND 797 799 ATP (By similarity).
 NP_BIND 843 848 ATP (By similarity).
 MOTIF 676 684 Nuclear localization signal.
 MOTIF 1032 1035 PPxY motif 1.
 MOTIF 1053 1056 PPxY motif 2.
 MOTIF 1298 1301 PPxY motif 3.
 MOTIF 1306 1308 PDZ-binding.
 ACT_SITE 843 843 Proton acceptor (By similarity).
 BINDING 751 751 ATP (By similarity).
 MOD_RES 875 875 Phosphotyrosine; by autocatalysis.
 MOD_RES 1035 1035 Phosphotyrosine; by autocatalysis.
 MOD_RES 1056 1056 Phosphotyrosine; by autocatalysis.
 MOD_RES 1150 1150 Phosphotyrosine; by autocatalysis.
 MOD_RES 1162 1162 Phosphotyrosine; by autocatalysis.
 MOD_RES 1188 1188 Phosphotyrosine; by autocatalysis.
 MOD_RES 1202 1202 Phosphotyrosine; by autocatalysis.
 MOD_RES 1242 1242 Phosphotyrosine; by autocatalysis.
 MOD_RES 1258 1258 Phosphotyrosine; by autocatalysis.
 MOD_RES 1284 1284 Phosphotyrosine; by autocatalysis.
 CARBOHYD 138 138 N-linked (GlcNAc...).
 CARBOHYD 174 174 N-linked (GlcNAc...).
 CARBOHYD 181 181 N-linked (GlcNAc...) (Potential).
 CARBOHYD 253 253 N-linked (GlcNAc...).
 CARBOHYD 358 358 N-linked (GlcNAc...).
 CARBOHYD 410 410 N-linked (GlcNAc...).
 CARBOHYD 473 473 N-linked (GlcNAc...).
 CARBOHYD 495 495 N-linked (GlcNAc...).
 CARBOHYD 548 548 N-linked (GlcNAc...) (Potential).
 CARBOHYD 576 576 N-linked (GlcNAc...).
 CARBOHYD 620 620 N-linked (GlcNAc...) (Potential).
 DISULFID 29 56
 DISULFID 156 186
 DISULFID 189 197
 DISULFID 193 205
 DISULFID 213 221
 DISULFID 217 229
 DISULFID 230 238
 DISULFID 234 246
 DISULFID 249 258
 DISULFID 262 289
 DISULFID 293 304
 DISULFID 308 323
 DISULFID 326 330
 DISULFID 503 512
 DISULFID 507 520
 DISULFID 523 532
 DISULFID 536 552
 DISULFID 555 569
 DISULFID 559 577
 DISULFID 580 589
 DISULFID 593 614
 DISULFID 617 625
 DISULFID 621 633  
Keyword
 3D-structure; Activator; Alternative splicing; Apoptosis; ATP-binding; Cell membrane; Complete proteome; Developmental protein; Disulfide bond; Glycoprotein; Kinase; Lactation; Membrane; Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Receptor; Reference proteome; Repeat; Signal; Transcription; Transcription regulation; Transferase; Transmembrane; Transmembrane helix; Tumor suppressor; Tyrosine-protein kinase; Ubl conjugation. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 1308 AA 
Protein Sequence
MKPATGLWVW VSLLVAAGTV QPSDSQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM 60
GNLEITSIEH NRDLSFLRSV REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF 120
LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNLTLVST 180
NGSSGCGRCH KSCTGRCWGP TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG 240
PKDTDCFACM NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD 300
SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS SNIDKFINCT 360
KINGNLIFLV TGIHGDPYNA IEAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL 420
VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST 480
INQRIVIRDN RKAENCTAEG MVCNHLCSSD GCWGPGPDQC LSCRRFSRGR ICIESCNLYD 540
GEFREFENGS ICVECDPQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA 600
NSFIFKYADP DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG 660
LFILVIVGLT FAVYVRRKSI KKKRALRRFL ETELVEPLTP SGTAPNQAQL RILKETELKR 720
VKVLGSGAFG TVYKGIWVPE GETVKIPVAI KILNETTGPK ANVEFMDEAL IMASMDHPHL 780
VRLLGVCLSP TIQLVTQLMP HGCLLEYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV 840
HRDLAARNVL VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ 900
SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY MVMVKCWMID 960
ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE 1020
EYLVPQAFNI PPPIYTSRAR IDSNRSEIGH SPPPAYTPMS GNQFVYRDGG FAAEQGVSVP 1080
YRAPTSTIPE APVAQGATAE IFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERS 1140
PRGELDEEGY MTPMRDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHN ASNGPPKAED 1200
EYVNEPLYLN TFANTLGKAE YLKNNILSMP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ 1260
EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTVLPPPP YRHRNTVV 1308 
Gene Ontology
 GO:0016323; C:basolateral plasma membrane; IDA:BHF-UCL.
 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005576; C:extracellular region; TAS:Reactome.
 GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
 GO:0005759; C:mitochondrial matrix; TAS:Reactome.
 GO:0005654; C:nucleoplasm; TAS:Reactome.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0004716; F:receptor signaling protein tyrosine kinase activity; IEA:InterPro.
 GO:0044212; F:transcription regulatory region DNA binding; IMP:UniProtKB.
 GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IDA:UniProtKB.
 GO:0061026; P:cardiac muscle tissue regeneration; ISS:UniProtKB.
 GO:0045165; P:cell fate commitment; IEA:Compara.
 GO:0008283; P:cell proliferation; TAS:ProtInc.
 GO:0021551; P:central nervous system morphogenesis; ISS:UniProtKB.
 GO:0009880; P:embryonic pattern specification; ISS:UniProtKB.
 GO:0007173; P:epidermal growth factor receptor signaling pathway; TAS:Reactome.
 GO:0008543; P:fibroblast growth factor receptor signaling pathway; TAS:Reactome.
 GO:0007507; P:heart development; ISS:UniProtKB.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0007595; P:lactation; IMP:UniProtKB.
 GO:0060749; P:mammary gland alveolus development; ISS:UniProtKB.
 GO:0060644; P:mammary gland epithelial cell differentiation; ISS:UniProtKB.
 GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; IMP:UniProtKB.
 GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
 GO:0008285; P:negative regulation of cell proliferation; IMP:UniProtKB.
 GO:0001755; P:neural crest cell migration; ISS:UniProtKB.
 GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
 GO:0021889; P:olfactory bulb interneuron differentiation; ISS:UniProtKB.
 GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
 GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
 GO:0060045; P:positive regulation of cardiac muscle cell proliferation; ISS:UniProtKB.
 GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
 GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; IDA:UniProtKB.
 GO:2000366; P:positive regulation of STAT protein import into nucleus; IMP:UniProtKB.
 GO:0045893; P:positive regulation of transcription, DNA-dependent; IMP:UniProtKB.
 GO:0042523; P:positive regulation of tyrosine phosphorylation of Stat5 protein; IMP:UniProtKB.
 GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
 GO:0030334; P:regulation of cell migration; ISS:UniProtKB.
 GO:0023014; P:signal transduction by phosphorylation; IEA:GOC.
 GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW. 
Interpro
 IPR000494; EGF_rcpt_L.
 IPR006211; Furin-like_Cys-rich_dom.
 IPR006212; Furin_repeat.
 IPR009030; Growth_fac_rcpt_N_dom.
 IPR011009; Kinase-like_dom.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
 IPR008266; Tyr_kinase_AS.
 IPR020635; Tyr_kinase_cat_dom.
 IPR016245; Tyr_kinase_EGF/ERB/XmrK_rcpt. 
Pfam
 PF00757; Furin-like
 PF07714; Pkinase_Tyr
 PF01030; Recep_L_domain 
SMART
 SM00261; FU
 SM00219; TyrKc 
PROSITE
 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00109; PROTEIN_KINASE_TYR 
PRINTS
 PR00109; TYRKINASE.