Dynamin 2 mediates PDGFRα-SHP-2-promoted glioblastoma growth and invasion

H. Feng, K. W. Liu, P. Guo, P. Zhang, T. Cheng, M. A. McNiven, G. R. Johnson, B. Hu, S. Y. Cheng

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

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-α (PDGFRα)-promoted glioma tumor growth and invasion. Here, we show that Dyn2 is an effector downstream of the PDGFRα-PI3K/SHP-2 signaling in glioma cells. Depletion of endogenous Dyn2 by short hairpin RNAs (shRNAs) inhibited PDGFRα-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 PDGFRα at the invasive fronts in PDGF-A-stimulated glioma cells. Inhibition of SHP-2 by siRNA knockdown abrogated Dyn2 association with activated PDGFRα and PDGFRα activation of Rac1 and Cdc42, and glioma cell migration, thereby establishing a link between SHP-2 interaction with Dyn2 and the PDGFRα signaling. Furthermore, a dominant-negative SHP-2 C459S mutant inhibited PDGF-A-stimulated glioma cell migration, phosphorylation of Dyn2 and concomitantly blocked PDGFRα-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 PDGFRα impaired PDGFRα-stimulated phosphorylation of Akt and Dyn2, and Dyn2 association with activated PDGFRα. Taken together, this study identifies Dyn2 as an effector that mediates PDGFRα-SHP-2-induced glioma tumor growth and invasion, suggesting that targeting the PDGFRα-SHP-2-Dyn2 pathway may be beneficial to patients with malignant glioblastomas.

Original languageEnglish (US)
Pages (from-to)2691-2702
Number of pages12
JournalOncogene
Volume31
Issue number21
DOIs
StatePublished - May 1 2012

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Keywords

  • Dyn2
  • PDGFRa
  • SHP-2
  • Src
  • glioma tumor growth
  • invasion

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Feng, H., Liu, K. W., Guo, P., Zhang, P., Cheng, T., McNiven, M. A., Johnson, G. R., Hu, B., & Cheng, S. Y. (2012). Dynamin 2 mediates PDGFRα-SHP-2-promoted glioblastoma growth and invasion. Oncogene, 31(21), 2691-2702. https://doi.org/10.1038/onc.2011.436