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Ref Type Journal Article
PMID (19718025)
Authors Prickett TD, Agrawal NS, Wei X, Yates KE, Lin JC, Wunderlich JR, Cronin JC, Cruz P, Rosenberg SA, Samuels Y
Title Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4.
Journal Vol Issue Date Pages Journal Short Title
Nature genetics 41 10 2009 Oct 1127-32 Nat Genet
URL
Abstract Text Tyrosine phosphorylation is important in signaling pathways underlying tumorigenesis. We performed a mutational analysis of the protein tyrosine kinase (PTK) gene family in cutaneous metastatic melanoma. We identified 30 somatic mutations affecting the kinase domains of 19 PTKs and subsequently evaluated the entire coding regions of the genes encoding these 19 PTKs for somatic mutations in 79 melanoma samples. We found ERBB4 mutations in 19% of individuals with melanoma and found mutations in two other kinases (FLT1 and PTK2B) in 10% of individuals with melanomas. We examined seven missense mutations in the most commonly altered PTK gene, ERBB4, and found that they resulted in increased kinase activity and transformation ability. Melanoma cells expressing mutant ERBB4 had reduced cell growth after shRNA-mediated knockdown of ERBB4 or treatment with the ERBB inhibitor lapatinib. These studies could lead to personalized therapeutics specifically targeting the kinases that are mutationally altered in individual melanomas.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
ERBB4 NCBI ALS19|HER4|p180erbB4 ERBB4, erb-b2 receptor tyrosine kinase 4, encodes HER4, an ERBB family member that plays a role in cell survival and differentiation (PMID: 12648466). ERBB4 activating mutations are frequent in melanoma and have been demonstrated in lung adenocarcinoma (PMID: 19718025, PMID: 26050618). Both: Oncogene and Tumor suppressor
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ERBB4 E317K missense gain of function ERBB4 E317K lies within the extracellular domain of the Erbb4 protein (UniProt.org). E317K results in activation of Akt but not Erk in a melanoma cell line in culture (PMID: 19718025) and activation of Erk but not Akt when expressed in the JM-a CYT2 isoform, and results in increased proliferation (PMID: 30044378), constitutive phosphorylation of Erbb4, and transformation in cell culture (PMID: 19718025), and tumor formation in a mouse model (PMID: 30044378).
ERBB4 E452K missense gain of function ERBB4 E452K lies within the extracellular domain of the Erbb4 protein (UniProt.org). E452K results in constitutive phosphorylation of Erbb4, increased Akt phosphorylation, and transformation in cell culture (PMID: 19718025).
ERBB4 E542K missense gain of function ERBB4 E542K lies within the extracellular domain of the Erbb4 protein (UniProt.org). E542K results in increased Erbb4 kinase activity and is transforming in cultured cells (PMID: 19718025).
ERBB4 E563K missense gain of function ERBB4 E563K lies within the extracellular domain of the Erbb4 protein (UniProt.org). E563K results in constitutive phosphorylation of Erbb4, increased cell proliferation and is transforming in cell culture (PMID: 19718025).
ERBB4 E836K missense gain of function ERBB4 E836K lies within the protein kinase domain of the Erbb4 protein (UniProt.org). E836K results in constitutive phosphorylation of Erbb4, increased cell proliferation and is transforming in cell culture (PMID: 19718025).
ERBB4 E872K missense gain of function ERBB4 E872K lies within the protein kinase domain of the Erbb4 protein (UniProt.org). E872K results in constitutive phosphorylation of Erbb4, increased cell proliferation and is transforming in cell culture (PMID: 19718025).
ERBB4 K751M missense loss of function ERBB4 K751M lies within the protein kinase domain of the Erbb4 protein (UniProt.org). K751M results in a loss of Erbb4 protein function as demonstrated by a loss of kinase activity in cell culture (PMID: 19718025, PMID: 21110957).
ERBB4 M313I missense unknown ERBB4 M313I lies within the extracellular domain of the Erbb4 protein (UniProt.org). M313I has been identified in sequencing studies (PMID: 19718025), but has not been biochemically characterized and therefore, its effect on Erbb4 protein function is unknown (PubMed, May 2026).
ERBB4 R544W missense gain of function ERBB4 R544W lies within the extracellular domain of the Erbb4 protein (UniProt.org). R544W results in constitutive phosphorylation of Erbb4, increased cell proliferation and is transforming in cell culture (PMID: 19718025).
ERBB4 Y111H missense unknown ERBB4 Y111H lies within the extracellular domain of the Erbb4 protein (UniProt.org). Y111H has been identified in the scientific literature (PMID: 20404484, PMID: 19718025), but has not been biochemically characterized and therefore, its effect on Erbb4 protein function is unknown (PubMed, May 2026).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB4 E563K melanoma sensitive Lapatinib Preclinical - Cell culture Actionable In a preclinical study, Tykerb (lapatinib) inhibited survival and induced apoptosis in melanoma cells harboring ERBB4 E563K in culture (PMID: 19718025). 19718025
ERBB4 E452K melanoma sensitive Lapatinib Preclinical - Cell culture Actionable In a preclinical study, Tykerb (lapatinib) inhibited growth and induced apoptosis in melanoma cells harboring ERBB4 E452K in culture (PMID: 19718025). 19718025
ERBB4 R544W melanoma sensitive Lapatinib Preclinical Actionable In a preclinical study, Tykerb (lapatinib) induced apoptosis in melanoma cells harboring ERBB4 R544W in culture (PMID: 19718025). 19718025
ERBB4 E317K melanoma sensitive Lapatinib Preclinical - Cell culture Actionable In a preclinical study, Tykerb (lapatinib) inhibited growth and induced apoptosis in melanoma cells harboring ERBB4 E317K in culture (PMID: 19718025). 19718025
ERBB4 R393W melanoma sensitive Lapatinib Preclinical - Cell culture Actionable In a preclinical study, Tykerb (lapatinib) inhibited survival of melanoma cells harboring ERBB4 R393W in culture (PMID: 19718025). 19718025