Molecule Information

General Information of the Molecule (ID: Mol00351)

• Name: Receptor tyrosine-protein kinase erbB-4 (ERBB4) ,Homo sapiens
• Synonyms: Proto-oncogene-like protein c-ErbB-4; Tyrosine kinase-type cell surface receptor HER4; p180erbB4; 4ICD; E4ICD; s80HER4; HER4
• Molecule Type: Protein
• Gene Name: ERBB4
• Gene ID: 2066
• Location: chr2:211375717-212538841[-]
• Sequence:
  MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVM
  GNLEITSIEHNRDLSFLRSVREVTGYVLVALNQFRYLPLENLRIIRGTKLYEDRYALAIF
  LNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVST
  NGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSG
  PKDTDCFACMNFNDSGACVTQCPQTFVYNPTTFQLEHNFNAKYTYGAFCVKKCPHNFVVD
  SSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCT
  KINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNL
  VTIGGRVLYSGLSLLILKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHTINWTTLFST
  INQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYD
  GEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGA
  NSFIFKYADPDRECHPCHPNCTQGCNGPTSHDCIYYPWTGHSTLPQHARTPLIAAGVIGG
  LFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKR
  VKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHL
  VRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEERRLV
  HRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQ
  SDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMID
  ADSRPKFKELAAEFSRMARDPQRYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAE
  EYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVP
  YRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERS
  PRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNPEYHNASNGPPKAED
  EYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQ
  EYSTKYFYKQNGRIRPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV
• 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 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.
• Uniprot ID: ERBB4_HUMAN
• Ensembl ID: ENSG00000178568
• HGNC ID: HGNC:3432

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioma [1]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: microRNA-127 silencing significantly affects cell growth and increases the sensitivity to adriamycin. microRNA-127 silencing arrests the cell cycle, potentiates adriamycin-induced apoptosis, and increases cellular Rh-123 uptake. microRNA-127 silencing down-regulates MDR1, MRP1, Runx2, Bcl-2, Survivin and ErbB4 expression while up-regulates p53 expression. microRNA-127 silencing inhibits AkT phosphorylation.

Oxaliplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colon cancer [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Resistant Drug: Oxaliplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-APC/PI Apoptosis assay
• Mechanism Description: Linc00152 modulates the expression of ERBB4 through competitively binding miR193a-3p. AkT activation mediated by ERBB4 contributes to Linc00152-conferred L-OHP resistance, Linc00152 contributed to L-OHP resistance at least partly through activating AkT pathway.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.19E-51; Fold-change: -8.38E-01; Z-score: -1.27E+00
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.83E-01; Fold-change: -3.16E-02; Z-score: -4.40E+00
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.18E-01; Fold-change: -5.17E-01; Z-score: -5.54E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.87E-01; Fold-change: -3.40E-01; Z-score: -1.38E+00

Colon cancer [ICD-11: 2B90]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Colon
• The Specified Disease: Colon cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.70E-01; Fold-change: -3.52E-03; Z-score: -2.03E-02
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 7.41E-07; Fold-change: -9.48E-02; Z-score: -5.22E-01

References

• Ref 1: Knockdown of microRNA-127 reverses adriamycin resistance via cell cycle arrest and apoptosis sensitization in adriamycin-resistant human glioma cells. Int J Clin Exp Pathol. 2015 Jun 1;8(6):6107-16. eCollection 2015.
• Ref 2: Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer. Mol Ther. 2016 Dec;24(12):2064-2077. doi: 10.1038/mt.2016.180. Epub 2016 Sep 16.