Proteolytic cleavage of protein tyrosine phosphatase mu regulates glioblastoma cell migration

Cancer Res. 2009 Sep 1;69(17):6960-8. doi: 10.1158/0008-5472.CAN-09-0863. Epub 2009 Aug 18.


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 mu (PTPmu) is a homophilic cell adhesion molecule. The full-length form of PTPmu is down-regulated in human glioblastoma. In this article, overexpression of full-length PTPmu is shown to suppress migration and survival of glioblastoma cells. Additionally, proteolytic cleavage is shown to be the mechanism of PTPmu down-regulation in glioblastoma cells. Proteolysis of PTPmu generates a series of proteolytic fragments, including a soluble catalytic intracellular domain fragment that translocates to the nucleus. Only proteolyzed PTPmu fragments are detected in human glioblastomas. Short hairpin RNA-mediated down-regulation of PTPmu fragments decreases glioblastoma cell migration and survival. A peptide inhibitor of PTPmu 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 PTPmu by proteolysis generates catalytically active PTPmu fragments that contribute to migration and survival of glioblastoma cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion / genetics
  • Cell Line, Tumor
  • Cell Movement* / genetics
  • Cell Survival / genetics
  • Central Nervous System Neoplasms / enzymology*
  • Central Nervous System Neoplasms / pathology
  • Central Nervous System Neoplasms / therapy
  • Down-Regulation
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / enzymology*
  • Glioblastoma / pathology
  • Glioblastoma / therapy
  • Humans
  • Hydrolysis
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Peptide Fragments / antagonists & inhibitors
  • Peptide Fragments / metabolism
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / antagonists & inhibitors*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / genetics*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism*


  • Enzyme Inhibitors
  • Peptide Fragments
  • RNA, Messenger
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2