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[摘要]：Protein kinase C iota (PKC iota) promotes non-small cell lung cancer (NSCLC) by binding to Par6 alpha and activating a Rac1-Pak-Mek1,2-Erk1,2 signaling cascade. The mechanism by which the PKC iota-Par6 alpha complex regulates Rac1 is unknown. Here we show that epithelial cell transforming sequence 2 (Ect2), a guanine nucleotide exchange factor for Rho family GTPases, is coordinately amplified and overexpressed with PKC iota in NSCLC tumors. RNA interference-mediated knockdown of Ect2 inhibits Rac1 activity and blocks transformed growth, invasion and tumorigenicity of NSCLC cells. Expression of constitutively active Rac1 (RacV12) restores transformation to Ect2-deficient cells. Interestingly, the role of Ect2 in transformation is distinct from its well-established role in cytokinesis. In NSCLC cells, Ect2 is mislocalized to the cytoplasm where it binds the PKC iota-Par6 alpha complex. RNA interference-mediated knockdown of either PKC iota or Par6 alpha causes Ect2 to redistribute to the nucleus, indicating that the PKC iota-Par6 alpha complex regulates the cytoplasmic localization of Ect2. Our data indicate that Ect2 and PKC iota are genetically and functionally linked in NSCLC, acting to coordinately drive tumor cell proliferation and invasion through formation of an oncogenic PKC iota-Par6 alpha-Ect2 complex. Oncogene (2009) 28, 3597-3607; doi:10.1038/onc.2009.217; published online 20 July 2009 |
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