Somatic mutations of ErbB4: selective loss-of-function phenotype affecting signal transduction pathways in cancer.
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.
Tvorogov
Denis
D
MediCity Research Laboratory and Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
Sundvall
Maria
M
Kurppa
Kari
K
Hollmén
Maija
M
Repo
Susanna
S
Johnson
Mark S
MS
Elenius
Klaus
K
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
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