Proteolytic Cleavage of Protein Tyrosine Phosphatase μ Regulates Glioblastoma Cell Migration

Glioblastoma multiforme (GBM), the most common malignant primary brain tumor, represents a significant disease burden. GRM tumor cells disperse extensively throughout the brat parenchyma, and the need for tumor-specific drug targets an pharmacologic agents to inhibit cell migration and dispersal is great. The receptor protein tyrosine phosphatase mu (PTP mu) is a homophilic cell adhesion molecule. The full-length form of PTP mu is down-regulated in human glioblastoma. In this article, overexpression of full-length PTP mu is shown to suppress migration and survival of glioblastoma cells. Additionally, proteolytic cleavage is shown to be the mechanism of PTP mu, down-regulation in glioblastoma cells. Proteolysis of PTP mu generates a series of proteolytic fragments, including a soluble catalytic intracellular domain fragment that translocates to the nucleus. Only proteolyzed PTP mu fragments are detected in human glioblastomas. Short hairpin RNA-mediated down-regulation of PTP mu fragments decreases glioblastoma cell migration and survival. A peptide inhibitor of PTP mu function blocks fragment-induced glioblastoma cell migration, which may prove to be of therapeutic value in GBM treatment. These data suggest that loss of cell surface PTP mu by proteolysis generates catalytically active PTP mu fragments that contribute to migration and survival of glioblastoma cells. [Cancer Res 2009;69(17):6960-8]