Dynamin 2 mediates PDGFR alpha-SHP-2-promoted glioblastoma growth and invasion

[摘要]：Dynamin 2 (Dyn2), a large GTPase, is involved in receptor tyrosine kinase (RTK)-promoted cell migration. However, the molecular mechanisms by which Dyn2 regulates RTK-induced cell migration have not been established. Recently, we reported that tyrosine-protein phosphatase non-receptor type 11 (SHP-2) and phosphatidylinositol 3-kinase (PI3K) mediate platelet-derived growth factor receptor-alpha (PDGFR alpha)-promoted glioma tumor growth and invasion. Here, we show that Dyn2 is an effector downstream of the PDGFR alpha-PI3K/SHP-2 signaling in glioma cells. Depletion of endogenous Dyn2 by short hairpin RNAs (shRNAs) inhibited PDGFR alpha-stimulated phosphorylation of Akt, Erk1/2, Rac1 and Cdc42 activities, glioma cell migration and survival in vitro and tumor growth and invasion in the brains of mice. Dyn2 binds to SHP-2 and PI3K and colocalizes with PDGFR alpha at the invasive fronts in PDGF-A-stimulated glioma cells. Inhibition of SHP-2 by siRNA knockdown abrogated Dyn2 association with activated PDGFR alpha and PDGFR alpha activation of Rac1 and Cdc42, and glioma cell migration, thereby establishing a link between SHP-2 interaction with Dyn2 and the PDGFR alpha signaling. Furthermore, a dominant-negative SHP-2 C459S mutant inhibited PDGF-A-stimulated glioma cell migration, phosphorylation of Dyn2 and concomitantly blocked PDGFR alpha-induced Src activation. Inhibition of Src by Src inhibitors attenuated PDGF-A-stimulated phosphorylation of Akt and Dyn2 and glioma cell migration. Additionally, mutations of binding sites to PI3K, SHP-2 or Src of PDGFR alpha impaired PDGFR alpha-stimulated phosphorylation of Akt and Dyn2, and Dyn2 association with activated PDGFR alpha. Taken together, this study identifies Dyn2 as an effector that mediates PDGFR alpha-SHP-2-induced glioma tumor growth and invasion, suggesting that targeting the PDGFR alpha-SHP-2-Dyn2 pathway may be beneficial to patients with malignant glioblastomas. Oncogene (2012) 31, 2691-2702; doi:10.1038/onc.2011.436; published online 26 September 2011

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