Proteolytic Cleavage of Protein Tyrosine Phosphatase μ Regulates Glioblastoma Cell Migration

被引:63
作者
Burgoyne, Adam M. [1 ]
Phillips-Mason, Polly J. [1 ]
Burden-Gulley, Susan M. [1 ]
Robinson, Shenandoah [2 ]
Sloan, Andrew E. [2 ]
Miller, Robert H. [3 ]
Brady-Kalnay, Susann M. [1 ,3 ]
机构
[1] Case Western Reserve Univ, Sch Med, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Dept Neurosurg, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA
关键词
SECRETASE-MEDIATED CLEAVAGE; PTP-MU; E-CADHERIN; HOMOPHILIC BINDING; CATENIN P120(CTN); MALIGNANT GLIOMAS; RPTP-MU; IN-VIVO; ADHESION; CANCER;
D O I
10.1158/0008-5472.CAN-09-0863
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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]
引用
收藏
页码:6960 / 6968
页数:9
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