Somatic mutations of ErbB4: selective loss-of-function phenotype affecting signal transduction pathways in cancer.
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Tvorogov D, Sundvall M, Kurppa K, Hollmen M, Repo S, Johnson MS, Elenius K
Somatic mutations of ErbB4: selective loss-of-function phenotype affecting signal transduction pathways in cancer.
J Biol Chem. 2009 Feb 27;284(9):5582-91. doi: 10.1074/jbc.M805438200. Epub 2008 Dec 19.
- PubMed ID
- 19098003 [ View in PubMed]
- 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.