Tvorogov Denis, Sundvall Maria, Kurppa Kari, Hollmén Maija, Repo Susanna, Johnson Mark S, Elenius Klaus
MediCity Research Laboratory and Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
J Biol Chem. 2009 Feb 27;284(9):5582-91. doi: 10.1074/jbc.M805438200. Epub 2008 Dec 19.
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.
目前临床正在使用针对表皮生长因子受体和ErbB2等ErbB受体的癌症药物。然而，ErbB4作为潜在癌症药物靶点的作用仍存在争议。最近，在乳腺癌、胃癌、结直肠癌或非小细胞肺癌患者中发现了改变ErbB4编码区的体细胞突变，但这些突变的功能意义尚不清楚。在此，我们证明，ErbB4的10个癌症相关突变中有2个会因破坏功能重要的结构特征而导致ErbB4激酶活性丧失。有趣的是，激酶失活的ErbB4突变体在与ErbB2形成异二聚体神经调节蛋白受体以及以ErbB2激酶依赖性方式促进Erk1/2和Akt磷酸化方面与野生型ErbB4一样有效。然而，突变的ErbB4受体无法使STAT5磷酸化，并抑制了MDA-MB-468乳腺癌细胞的分化。这些发现表明，体细胞ErbB4突变具有功能后果，并导致ErbB4信号传导的选择性变化。
