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

Oncogene volume 31, pages 2691–2702 (2012)Cite this article

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.

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Acknowledgements

We thank Drs Y Zhou and E Van Meir for providing glioma cell lines and Dr H Damke and L Vance for proofreading of this manuscript. This work was supported in part by a grant from ACS (RSG CSM-107144), grants from NIH (CA130966), a grant with the Pennsylvania Department of Health, and Innovative Research Scholar Awards of the Hillman Foundation to SY Cheng and B Hu, and a James S McDonnell Foundation Researching Award in Brain Cancer to B Hu.

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Authors and Affiliations

  1. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    H Feng, K W Liu, P Guo, B Hu & S Y Cheng

  2. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA

    H Feng, K W Liu, P Guo & S Y Cheng

  3. Division of Pediatric General and Thoracic Surgery, Children's Hospital, Pittsburgh, PA, USA

    P Guo

  4. Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA

    P Zhang & T Cheng

  5. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    T Cheng

  6. Department of Biochemistry and Molecular Biology and Center for Basic Research in Digestive Diseases, Mayo Clinic, Rochester, MN, USA

    M A McNiven

  7. Division of Therapeutic Proteins and Center for Drug Evaluation and Research, Laboratory of Chemistry, Food and Drug Administration, Bethesda, MD, USA

    G R Johnson

  8. Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    B Hu

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  1. H Feng
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Correspondence to B Hu or S Y Cheng.

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Feng, H., Liu, K., Guo, P. et al. Dynamin 2 mediates PDGFRα-SHP-2-promoted glioblastoma growth and invasion. Oncogene 31, 2691–2702 (2012). https://doi.org/10.1038/onc.2011.436

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