title: Somatic mutations of ErbB4: selective loss-of-function phenotype affecting signal transduction pathways in cancer.
abstract: Cancer drugs targeting ErbB receptors, such as epidermal growth factor receptor and ErbB2, are currently in clinical use. However, the role of ErbB4 as a potential cancer drug target has remained controversial. Recently, somatic mutations altering the coding region of ErbB4 were described in patients with breast, gastric, colorectal, or non-small cell lung cancer, but the functional significance of these mutations is unknown. Here we demonstrate that 2 of 10 of the cancer-associated mutations of ErbB4 lead to loss of ErbB4 kinase activity due to disruption of functionally important structural features. Interestingly, the kinase-dead ErbB4 mutants were as efficient as wild-type ErbB4 in forming a heterodimeric neuregulin receptor with ErbB2 and promoting phosphorylation of Erk1/2 and Akt in an ErbB2 kinase-dependent manner. However, the mutant ErbB4 receptors failed to phosphorylate STAT5 and suppressed differentiation of MDA-MB-468 mammary carcinoma cells. These findings suggest that the somatic ErbB4 mutations have functional consequences and lead to selective changes in ErbB4 signaling.
authors.affiliation: MediCity Research Laboratory and Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
authors.forename: Denis
authors.initials: D
authors.lastname: Tvorogov
authors.forename: Maria
authors.initials: M
authors.lastname: Sundvall
authors.forename: Kari
authors.initials: K
authors.lastname: Kurppa
authors.forename: Maija
authors.initials: M
authors.lastname: Hollmén
authors.forename: Susanna
authors.initials: S
authors.lastname: Repo
authors.forename: Mark S
authors.initials: MS
authors.lastname: Johnson
authors.forename: Klaus
authors.initials: K
authors.lastname: Elenius
mesh_terms: D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D066247:Receptor, ErbB-4; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D050799:STAT5 Transcription Factor; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human