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Anaplastic lymphoma kinase activates the small GTPase Rap1 via the Rap1-specific GEF C3G in both neuroblastoma and PC12 cells

Oncogene volume 29, pages 2817–2830 (2010)Cite this article

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Abstract

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.

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Acknowledgements

We thank Caroline Grabbe for comments and critical reading of the paper and Lovisa Olofsson for initial experiments. BH is supported by a Grant (08-0597) from the Swedish Cancer Foundation, Lions Cancer Research Foundation, Umeå, and Grant (08/084) from the Swedish Childhood Cancer Foundation. RHP is a Swedish Cancer Foundation Research Fellow and is supported by grants from the Swedish Research Council (621-2003-3399), the Swedish Childhood Cancer Foundation (08/074) and the Association for International Cancer Research (AICR 08-0177).

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  1. Department of Molecular Biology, Umeå University, Umeå, Sweden

    C Schönherr, R H Palmer & B Hallberg

  2. College of Biological Sciences and Biotechnology, Beijing Forestry University, Beijing, China

    H-L Yang

  3. U839 INSERM/UPMC IFM, Paris, France

    M Vigny

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  1. C Schönherr
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Schönherr, C., Yang, HL., Vigny, M. et al. Anaplastic lymphoma kinase activates the small GTPase Rap1 via the Rap1-specific GEF C3G in both neuroblastoma and PC12 cells. Oncogene 29, 2817–2830 (2010). https://doi.org/10.1038/onc.2010.27

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