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 (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.

Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis

“…1C and Fig. S2B) (12). Phosphorylation on Y 1811 was not directly regulated by HER2 but instead mediated by SRC protein kinases ( Fig.…”

“…Studies in cell lines, including breast cancer, also established that mammalian DOCK1 is a regulator of cell migration and invasion downstream of integrin signaling (11). The DOCK1-Rac pathway was uncovered to promote glioblastoma cell migration driven by oncogenic RTKs including the PDGFR and the EGFR variant type III (12,13). Both receptors orchestrate tyrosine phosphorylation of DOCK1 to increase its GEF activity.…”

Molecular Mechanisms of Glioma Cell Motility

“…In GBM, two members of the TNF receptor superfamily act through RAC-1: TNF-like weak inducer of apoptosis (TWEAK) and TNF receptor superfamily member 19 (TROY) (99,102). EGFRvIII, a truncated and constitutively active EGF receptor, and Platelet Growth Factor Receptor alpha (PDGFRa) activate RAC-1-mediated migration through tyrosine protein kinase SRC-dependent DOCK180 phosphorylation (103,104). RAC-1 is also activated by the IQ-domain GTPase-Activating Protein (IQGAP)-1/ADP-Ribosylation Factor 6 (ARF6), neurotensin, and ephrinB3 signaling (105)(106)(107).…”

“…RAC-1 is also activated by the IQ-domain GTPase-Activating Protein (IQGAP)-1/ADP-Ribosylation Factor 6 (ARF6), neurotensin, and ephrinB3 signaling (105)(106)(107). RAC-1 activity is further modulated by CDC42 (104,108) as well as by axonal guidance molecules (see the section "Axonal Guidance Molecules"). RhoA activity correlates with increased glioma cell migration.…”

NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer

“…55,56 BCAR1 signaling has also been associated with cell proliferation, survival, and migration/invasion in many tumor types besides breast cancer, including ovarian and prostate cancer, glioblastoma, melanoma, and hematopoietic malignancies. 11,12,17,27,[57][58][59][60][61][62][63] Accordingly, a great abundance of BCAR1 tyrosine-and serine/threonine-phosphorylated peptides have been detected in a wide variety of cancers (phosphosite.org) (Fig. 1).…”