Target Information
Target General Infomation | |||||
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Target ID |
T92057
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Former ID |
TTDC00114
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Target Name |
Receptor protein-tyrosine kinase erbB-4
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Gene Name |
ERBB4
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Synonyms |
P180erbB4; Tyrosine kinase-type cell surface receptor HER4; ERBB4
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Target Type |
Clinical Trial
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Disease | Cancer [ICD9: 140-229; ICD10: C00-C96] | ||||
Hematological malignancies [ICD9: 200-209; ICD10: C81-C86] | |||||
Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86] | |||||
Non-small cell lung cancer [ICD10: C33-C34] | |||||
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48] | |||||
Function |
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 fornormal 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.
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BioChemical Class |
Kinase
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Target Validation |
T92057
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UniProt ID | |||||
EC Number |
EC 2.7.10.1
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Sequence |
MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVM
GNLEITSIEHNRDLSFLRSVREVTGYVLVALNQFRYLPLENLRIIRGTKLYEDRYALAIF LNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVST NGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSG PKDTDCFACMNFNDSGACVTQCPQTFVYNPTTFQLEHNFNAKYTYGAFCVKKCPHNFVVD SSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCT KINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNL VTIGGRVLYSGLSLLILKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHTINWTTLFST INQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYD GEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGA NSFIFKYADPDRECHPCHPNCTQGCNGPTSHDCIYYPWTGHSTLPQHARTPLIAAGVIGG LFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKR VKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHL VRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEERRLV HRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQ SDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMID ADSRPKFKELAAEFSRMARDPQRYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAE EYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVP YRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERS PRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNPEYHNASNGPPKAED EYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQ EYSTKYFYKQNGRIRPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV |
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Structure |
2AHX; 2L2T; 2LCX; 2R4B; 3BBT; 3BBW;3BCE; 3U2P; 3U7U; 3U9U; 2AHX; 2L2T; 2LCX; 2R4B; 3BBT;3BBW; 3BCE; 3U2P; 3U7U; 3U9U
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Drugs and Mode of Action | |||||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
Pathways | |||||
KEGG Pathway | ErbB signaling pathway | ||||
Calcium signaling pathway | |||||
Endocytosis | |||||
Proteoglycans in cancer | |||||
PANTHER Pathway | Alzheimer disease-presenilin pathway | ||||
Cadherin signaling pathway | |||||
EGF receptor signaling pathway | |||||
WikiPathways | ErbB Signaling Pathway | ||||
EV release from cardiac cells and their functional effects | |||||
References | |||||
Ref 522319 | ClinicalTrials.gov (NCT00676299) A Safety and Dose-finding Study of JNJ-26483327, a Drug in Development for Cancer, for Patients With Advanced and/or Refractory Solid Malignancies.. U.S. National Institutes of Health. | ||||
Ref 523496 | ClinicalTrials.gov (NCT01360554) ARCHER 1009 : A Study Of Dacomitinib (PF-00299804) Vs. Erlotinib In The Treatment Of Advanced Non-Small Cell Lung Cancer. U.S. National Institutes of Health. | ||||
Ref 525138 | ClinicalTrials.gov (NCT02407080) Open Label Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia. U.S. National Institutes of Health. | ||||
Ref 525738 | Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem. 2000 Apr 6;43(7):1380-97. | ||||
Ref 532608 | Therapeutic targeting of EPH receptors and their ligands. Nat Rev Drug Discov. 2014 Jan;13(1):39-62. | ||||
Ref 528037 | J Med Chem. 2006 Feb 23;49(4):1475-85.Tyrosine kinase inhibitors. 19. 6-Alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB family of tyrosine kinase receptors. | ||||
Ref 532836 | Discovery of a series of 2,5-diaminopyrimidine covalent irreversible inhibitors of Bruton's tyrosine kinase with in vivo antitumor activity. J Med Chem. 2014 Jun 26;57(12):5112-28. | ||||
Ref 536251 | A phase I clinical and pharmacokinetic study of oral CI-1033 in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4274-82. | ||||
Ref 536474 | A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22. | ||||
Ref 542446 | (http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7422). |
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