Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTWALCO)

• DTT Name: HER4 messenger RNA (ERBB4 mRNA)
• Synonyms: Tyrosine kinase-type cell surface receptor HER4 (mRNA); Receptor tyrosine-protein kinase erbB-4 (mRNA); Proto-oncogene-like protein c-ErbB-4 (mRNA); P180erbB4 (mRNA); HER4 (mRNA)
• Gene Name: ERBB4
• DTT Type: Literature-reported target; [1]
• BioChemical Class: mRNA target
• UniProt ID: ERBB4_HUMAN
• TTD ID: T06559
• EC Number: EC 2.7.10.1
• Sequence:
  MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVM
  GNLEITSIEHNRDLSFLRSVREVTGYVLVALNQFRYLPLENLRIIRGTKLYEDRYALAIF
  LNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVST
  NGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSG
  PKDTDCFACMNFNDSGACVTQCPQTFVYNPTTFQLEHNFNAKYTYGAFCVKKCPHNFVVD
  SSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCT
  KINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNL
  VTIGGRVLYSGLSLLILKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHTINWTTLFST
  INQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYD
  GEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGA
  NSFIFKYADPDRECHPCHPNCTQGCNGPTSHDCIYYPWTGHSTLPQHARTPLIAAGVIGG
  LFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKR
  VKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHL
  VRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEERRLV
  HRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQ
  SDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMID
  ADSRPKFKELAAEFSRMARDPQRYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAE
  EYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVP
  YRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERS
  PRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNPEYHNASNGPPKAED
  EYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQ
  EYSTKYFYKQNGRIRPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV
• Function: 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. 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.
• KEGG Pathway:
  ErbB signaling pathway (hsa04012)
  Calcium signaling pathway (hsa04020)
  Endocytosis (hsa04144)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  Signaling by ERBB4 (R-HSA-1236394)
  SHC1 events in ERBB2 signaling (R-HSA-1250196)
  PI3K events in ERBB4 signaling (R-HSA-1250342)
  SHC1 events in ERBB4 signaling (R-HSA-1250347)
  Nuclear signaling by ERBB4 (R-HSA-1251985)
  Downregulation of ERBB4 signaling (R-HSA-1253288)
  PIP3 activates AKT signaling (R-HSA-1257604)
  GRB2 events in ERBB2 signaling (R-HSA-1963640)
  PI3K events in ERBB2 signaling (R-HSA-1963642)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  RAF/MAP kinase cascade (R-HSA-5673001)
  ERBB2 Regulates Cell Motility (R-HSA-6785631)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  ERBB2 Activates PTK6 Signaling (R-HSA-8847993)
  Downregulation of ERBB2 signaling (R-HSA-8863795)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Long-term potentiation (R-HSA-9620244)
  Signaling by ERBB2 KD Mutants (R-HSA-9664565)
  Signaling by ERBB2 TMD/JMD mutants (R-HSA-9665686)
  Signaling by ERBB2 (R-HSA-1227986)

Molecular Interaction Atlas (MIA) of This DTT

13 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CL-387785	DMLKFZC	Discovery agent	N.A.	Investigative	[2]
ISIS 19634	DMVOSN1	Discovery agent	N.A.	Investigative	[1]
ISIS 19639	DMAW4OE	Discovery agent	N.A.	Investigative	[1]
ISIS 19647	DMS5PZ0	Discovery agent	N.A.	Investigative	[1]
ISIS 19649	DMBEPGU	Discovery agent	N.A.	Investigative	[1]
ISIS 19650	DMCZLK1	Discovery agent	N.A.	Investigative	[1]
ISIS 19651	DM8O7EM	Discovery agent	N.A.	Investigative	[1]
ISIS 19657	DMGIMH8	Discovery agent	N.A.	Investigative	[1]
ISIS 19658	DM8WC4A	Discovery agent	N.A.	Investigative	[1]
ISIS 19659	DMQ5UA3	Discovery agent	N.A.	Investigative	[1]
ISIS 19675	DMB5LNC	Discovery agent	N.A.	Investigative	[1]
ISIS 19676	DMYEMST	Discovery agent	N.A.	Investigative	[1]
ISIS 19677	DMN0DR2	Discovery agent	N.A.	Investigative	[1]

References

• [1] US patent application no. 6,255,111, Antisense modulation of Her-4 expression.
• [2] Tyrosine kinase inhibitors. 19. 6-Alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB... J Med Chem. 2006 Feb 23;49(4):1475-85.