Department of Molecular Biology, Umeå University, Umeå, Sweden.
Oncogene. 2010 May 13;29(19):2817-30. doi: 10.1038/onc.2010.27. Epub 2010 Mar 1.
Many different types of cancer originate from aberrant signaling from the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK), arising through different translocation events and overexpression. Further, activating point mutations in the ALK domain have been recently reported in neuroblastoma. To characterize signaling in the context of the full-length receptor, we have examined whether ALK is able to activate Rap1 and contribute to differentiation/proliferation processes. We show that ALK activates Rap1 via the Rap1-specific guanine-nucleotide exchange factor C3G, which binds in a constitutive complex with CrkL to activated ALK. The activation of the C3G/Rap1 pathway results in neurite outgrowth of PC12 cells, which is inhibited by either overexpression of Rap1GAP or siRNA-mediated knockdown of Rap1 itself or the guanine nucleotide exchange factor C3G. Significantly, this pathway also appears to function in the regulation of proliferation of neuroblastoma cells such as SK-N-SH and SH-SY5Y, because abrogation of Rap1 activity by Rap1-specific siRNA or overexpression of Rap1GAP reduces cellular growth. These results suggest that ALK activation of Rap1 may contribute to cell proliferation and oncogenesis of neuroblastoma driven by gain-of-function mutant ALK receptors.
许多不同类型的癌症源于间变性淋巴瘤激酶（ALK）受体酪氨酸激酶（RTK）的异常信号，这些信号通过不同的易位事件和过表达产生。此外，最近在神经母细胞瘤中报道了 ALK 结构域的激活点突变。为了在全长受体的背景下描述信号转导，我们研究了 ALK 是否能够激活 Rap1 并有助于分化/增殖过程。我们表明，ALK 通过 Rap1 特异性鸟苷酸交换因子 C3G 激活 Rap1，C3G 与 CrkL 结合形成与激活的 ALK 组成型复合物。C3G/Rap1 通路的激活导致 PC12 细胞的轴突生长，这可以被 Rap1GAP 的过表达或 Rap1 本身或鸟苷酸交换因子 C3G 的 siRNA 介导的敲低抑制。重要的是，该通路似乎也在神经母细胞瘤细胞如 SK-N-SH 和 SH-SY5Y 的增殖调控中起作用，因为 Rap1 特异性 siRNA 或 Rap1GAP 的过表达使 Rap1 活性失活会降低细胞生长。这些结果表明，ALK 激活 Rap1 可能有助于由功能获得性突变 ALK 受体驱动的神经母细胞瘤的细胞增殖和致癌作用。
