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Proteolytic Cleavage of Protein Tyrosine Phosphatase µ Regulates Glioblastoma Cell Migration

Departments of ¹ Molecular Biology and Microbiology, ² Neurosurgery, and ³ Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio

Requests for reprints: Susann M. Brady-Kalnay, Department of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4960. Phone: 216-368-0330; Fax: 216-368-3055; E-mail: susann.brady-kalnay{at}case.edu.

Key Words: protein tyrosine phosphatase • PTPµ • glioblastoma • cell migration • proteolysis

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