title: Activating ERBB4 mutations in non-small cell lung cancer.
abstract: Recent efforts to comprehensively characterize the mutational landscape of non-small cell lung cancer have identified frequent mutations in the receptor tyrosine kinase ERBB4. However, the significance of mutated ERBB4 in non-small cell lung cancer remains elusive. Here, we have functionally characterized nine ERBB4 mutations previously identified in lung adenocarcinoma. Four out of the nine mutations, Y285C, D595V, D931Y and K935I, were found to be activating, increasing both basal and ligand-induced ErbB4 phosphorylation. According to structural analysis, the four activating mutations were located at critical positions at the dimerization interfaces of the ErbB4 extracellular (Y285C and D595V) and kinase (D931Y and K935I) domains. Consistently, the mutations enhanced ErbB4 dimerization and increased the trans activation in ErbB4 homodimers and ErbB4-ErbB2 heterodimers. The expression of the activating ERBB4 mutants promoted survival of NIH 3T3 cells in the absence of serum. Interestingly, serum starvation of NIH 3T3 cells expressing the ERBB4 mutants only moderately increased the phosphorylation of canonical ErbB signaling pathway effectors Erk1/2 and Akt as compared with wild-type ERBB4. In contrast, the mutations clearly enhanced the proteolytic release of signaling-competent ErbB4 intracellular domain. These results suggest the presence of activating driver mutations of ERBB4 in non-small cell lung cancer.
authors.affiliation: MediCity Research Laboratories, Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.|Turku Doctoral Programme of Molecular Medicine, Turku, Finland.
authors.forename: K J
authors.initials: KJ
authors.lastname: Kurppa
authors.affiliation: Structural Bioinformatics Laboratory, Biochemistry, Faculty of Sciences and Engineering, Åbo Akademi University, Turku, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Denessiouk
authors.affiliation: Structural Bioinformatics Laboratory, Biochemistry, Faculty of Sciences and Engineering, Åbo Akademi University, Turku, Finland.
authors.forename: M S
authors.initials: MS
authors.lastname: Johnson
authors.affiliation: MediCity Research Laboratories, Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.|Department of Oncology, Turku University Hospital, Turku, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Elenius
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics*; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D005110:Extracellular Space / Q000201:enzymology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D066247:Receptor, ErbB-4 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D066247:Receptor, ErbB-4