Abstract
Glioblastoma (GBM) is an invasive brain cancer with tumor cells that disperse from the primary mass escaping surgical resection, displaying resistance to chemotherapy and radiation, and invariably giving rise to lethal recurrent lesions. Targeted therapies such as the anti-vascular endothelial growth factor (VEGF) blocking antibody bevacizumab have yielded disappointing results in GBM clinical trials, with no improvements in overall patient survival. Many patients treated with bevacizumab develop acquired resistance leading to lethal recurrent lesions associated with robust tumor cell invasion. While a great deal is known about genes and pathways that promote GBM proliferation and neovascularization, relatively little is understood about mechanisms that drive GBM cell invasion during progression or following anti-angiogenic therapy. Here, we report that PTP-PEST, a cytoplasmic protein tyrosine phosphatase encoded by the PTPN12 gene, controls GBM cell invasion by physically bridging the focal adhesion protein Crk-associated substrate (Cas) to valosin containing protein (Vcp), an ATP-dependent protein segregase that selectively extracts ubiquitinated proteins from multiprotein complexes and targets them for degradation via the ubiquitin proteasome system. Both Cas and Vcp are substrates for PTP-PEST, with the phosphorylation status of tyrosine 805 (Y805) in Vcp impacting affinity for Cas in focal adhesions and controlling ubiquitination levels and protein stability. Perturbing PTP-PEST-mediated phosphorylation of Cas and Vcp led to alterations in GBM cell invasive growth in vitro and in pre-clinical mouse models generated with GBM stem cells. Furthermore, acquired resistance to bevacizumab correlates with reduced expression of PTP-PEST in invasive GBM cells. Collectively, these data reveal a novel regulatory mechanism involving PTP-PEST, Vcp, and Cas that dynamically balances phosphorylation-dependent ubiquitination of key focal proteins involved in GBM cell invasion.