Abstract 4314: Dynamin 2 mediates PDGFRα-SHP-2-promoted glioblastoma growth and invasion

Abstract

Abstract Dynamin 2 (Dyn2), a large GTPase, is involved in receptor tyrosine kinase (RTK)-promoted cell migration. However, molecular mechanisms by which Dyn2 regulates RTK-induced cell migration have not been established. Recently we reported that SHP-2 and PI3K mediate PDGFR[[Unsupported Character - Symbol Font α]]-promoted glioma tumor growth and invasion. Here, we show that Dyn2 is an effector downstream of the PDGFR[[Unsupported Character - Symbol Font α]]-PI3K/SHP-2 signaling in glioma cells. Depletion of endogenous Dyn2 by shRNAs inhibited PDGFR[[Unsupported Character - Symbol Font α]]-stimulated phosphorylation of Akt, Erk1/2, Rac1 and Cdc42 activities, glioma cell migration and survival in vitro, tumor growth and invasion in the brains of mice. Dyn2 binds to SHP-2, PI3K and co-localizes with PDGFR[[Unsupported Character - Symbol Font α]] at the invasive fronts in PDGF-A-stimulated glioma cells. Inhibition of SHP-2 by siRNA knockdown abrogated Dyn2 association with activated PDGFR[[Unsupported Character - Symbol Font α]] and PDGFR[[Unsupported Character - Symbol Font α]] activation of Rac1 and Cdc42, glioma cell migration, thereby establishing a link between SHP-2 interaction with Dyn2 and the PDGFR[[Unsupported Character - Symbol Font α]] signaling. Furthermore, a dominant negative SHP-2 C459S mutant inhibited PDGF-A-stimulated glioma cell migration, phosphorylation of Dyn2 and concomitantly blocked PDGFR[[Unsupported Character - Symbol Font α]]-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[[Unsupported Character - Symbol Font α]] impaired PDGFR[[Unsupported Character - Symbol Font α]]-stimulated phosphorylation of Akt and Dyn2, and Dyn2 association with activated PDGFR[[Unsupported Character - Symbol Font α]]. Taken together, this study identifies Dyn2 as an effector that mediates PDGFR[[Unsupported Character - Symbol Font α]]-SHP-2-induced glioma tumor growth and invasion, suggesting that targeting the PDGFR[[Unsupported Character - Symbol Font α]]-SHP-2-Dyn2 pathway may be beneficial to patients with malignant glioblastomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4314. doi:1538-7445.AM2012-4314