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 patient...

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Bibliographic Details
Published in:The Journal of biological chemistry 2009-02, Vol.284 (9), p.5582-5591
Main Authors: Tvorogov, Denis, Sundvall, Maria, Kurppa, Kari, Hollmén, Maija, Repo, Susanna, Johnson, Mark S, Elenius, Klaus
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Cell Culture Techniques
Cell Differentiation
Cell Proliferation
Chlorocebus aethiops
COS Cells
ErbB Receptors - genetics
ErbB Receptors - metabolism
Humans
Immunoprecipitation
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3 - metabolism
Models, Molecular
Mutation - genetics
Phenotype
Phosphorylation
Proto-Oncogene Proteins c-akt - metabolism
Receptor, ErbB-2 - metabolism
Receptor, ErbB-4
Signal Transduction
STAT5 Transcription Factor - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M805438200