Activation of Rac1 by Src-dependent phosphorylation of Dock180(Y1811) 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 (Dock180(Y1811)) 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 Dock180(Y1811F) abrogated, whereas an RNAi-resistant Dock180(WT) rescued, PDGFRα-promoted glioma growth, survival, and invasion. Phosphorylation of Dock180(Y1811) enhanced its association with CrkII and p130(Cas), causing activation of Rac1 and consequent cell motility. Dock180 also associated with PDGFRα to promote cell migration. Finally, phosphorylated Dock180(Y1811) was detected in clinical samples of gliomas and various types of human cancers, and coexpression of phosphorylated Dock180(Y1811), phosphorylated Src(Y418), 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 Dock180(Y1811) 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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 121 Issue 12 Pg. 4670-84 (Dec 2011) ISSN: 1558-8238 [Electronic] United States
• PMID: 22080864 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DOCK1 protein, human
• Neoplasm Proteins
• Proto-Oncogene Proteins c-crk
• RAC1 protein, human
• Recombinant Fusion Proteins
• Receptor, Platelet-Derived Growth Factor alpha
• src-Family Kinases
• rac GTP-Binding Proteins
• rac1 GTP-Binding Protein

Topics

• Animals
• Brain Neoplasms (enzymology, genetics, metabolism, pathology)
• Cell Line, Tumor (metabolism, transplantation)
• Cell Movement
• Enzyme Activation
• Gene Amplification
• Gene Expression Profiling
• Glioblastoma (enzymology, genetics, metabolism, pathology)
• Humans
• Mice
• Neoplasm Invasiveness
• Neoplasm Proteins (physiology)
• Phosphorylation
• Prognosis
• Protein Processing, Post-Translational
• Proto-Oncogene Proteins c-crk (metabolism)
• RNA Interference
• Receptor, Platelet-Derived Growth Factor alpha (genetics, physiology)
• Recombinant Fusion Proteins (immunology, metabolism)
• Transplantation, Heterologous
• rac GTP-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• rac1 GTP-Binding Protein (physiology)
• src-Family Kinases (metabolism)