Activation of Rac1 by Src-dependent phosphorylation of Dock180Y1811 mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans
Haizhong Feng, … , Webster K. Cavenee, Shi-Yuan Cheng
Haizhong Feng, … , Webster K. Cavenee, Shi-Yuan Cheng
Published November 14, 2011
Citation Information: J Clin Invest. 2011;121(12):4670-4684. https://doi.org/10.1172/JCI58559.
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Research Article Oncology

Activation of Rac1 by Src-dependent phosphorylation of Dock180Y1811 mediates PDGFRα-stimulated glioma tumorigenesis in mice and humans

Abstract

Two hallmarks of glioblastoma multiforme, the most common malignant brain cancer in humans, are aggressive growth and the ability of single glioma cells to disperse throughout the brain. These characteristics render tumors resistant to current therapies and account for the poor prognosis of patients. Although it is known that oncogenic signaling caused by overexpression of genes such as PDGFRA is responsible for robust glioma growth and cell infiltration, the mechanisms underlying glioblastoma malignancy remain largely elusive. Here, we report that PDGFRα signaling in glioblastomas leads to Src-dependent phosphorylation of the guanine nucleotide exchange factor Dock180 at tyrosine 1811 (Dock180Y1811) that results in activation of the GTPase Rac1 and subsequent cell growth and invasion. In human glioma cells, knockdown of Dock180 and reversion with an RNAi-resistant Dock180Y1811F abrogated, whereas an RNAi-resistant Dock180WT rescued, PDGFRα-promoted glioma growth, survival, and invasion. Phosphorylation of Dock180Y1811 enhanced its association with CrkII and p130Cas, causing activation of Rac1 and consequent cell motility. Dock180 also associated with PDGFRα to promote cell migration. Finally, phosphorylated Dock180Y1811 was detected in clinical samples of gliomas and various types of human cancers, and coexpression of phosphorylated Dock180Y1811, phosphorylated SrcY418, and PDGFRα was predictive of extremely poor prognosis of patients with gliomas. Taken together, our findings provide insight into PDGFRα-stimulated gliomagenesis and suggest that phosphorylated Dock180Y1811 contributes to activation of Rac1 in human cancers with PDGFRA amplification.

Authors

Haizhong Feng, Bo Hu, Kun-Wei Liu, Yanxin Li, Xinghua Lu, Tao Cheng, Jia-Jean Yiin, Songjian Lu, Susan Keezer, Tim Fenton, Frank B. Furnari, Ronald L. Hamilton, Kristiina Vuori, Jann N. Sarkaria, Motoo Nagane, Ryo Nishikawa, Webster K. Cavenee, Shi-Yuan Cheng

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Figure 5

p-Y of Dock180Y1811 regulates PDGFRα-stimulated recruitment of CrkII and p130Cas and activity of Rac1.

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p-Y of Dock180Y1811 regulates PDGFRα-stimulated recruitment of CrkII and...
(A) PDGF-A induced p-Y of PDGFRα and Dock180, but not Dock180Y1811F, and protein association of Dock180WT, but not Dock180Y1811F, with CrkII and p130Cas. (B) PDGF-A induced the formation of a Dock180/CrkII/p130Cas complex and activated Rac1 in LN443 and LN444 cells stimulated by PDGF-A. (C) Reexpression of shRNA-resistant Flag-tagged Dock180WT*, but not Dock180Y1811F*, restored the PDGF-A–induced formation of a Dock180/CrkII/p130Cas complex and activation of Rac1 in LN444/PDGF-A/shDock180 glioma cells. (A–C) p-Y of Dock180 was detected with a pan-phosphotyrosine antibody (4G10). Relative p-Y of Dock180, CrkII, or p130Cas was determined by Image J and normalized to the amount of Dock180 in IP. *P < 0.05. Data (± SD) represent 3 independent experiments with similar results.