The protein tyrosine phosphatase TCPTP suppresses the tumorigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor

Glioblastoma multiforme (GBM) is the most aggressive type of glioma and GBM s frequently contain amplifications or mutations of the EGFR gene. The most common mutation results in a truncated receptor tyrosine kinase known as D elta EGFR that signals constitutively and promotes GBM growth. Here, we rep ort that the 45-kDa variant of the protein tyrosine phosphatase TCPTP (TC45 ) can recognize Delta EGFR as a cellular substrate. TC45 dephosphorylated D elta EGFR in U87MG glioblastoma cells and inhibited mitogen-activated prote in kinase ERK2 and phosphatidylinositol 3-kinase signaling. In contrast, th e substrate-trapping TC45-D182A mutant, which is capable of forming stable complexes with TC45 substrates, suppressed the activation of ERK2 but not p hosphatidylinositol 3-kinase. TC45 inhibited the proliferation and anchorag e-independent growth of Delta EGFR cells but TC45-D182A only inhibited cell ular proliferation. Notably, neither TC45 nor TC45-D182A inhibited the prol iferation of U87MG cells that did not express Delta EGFR. Delta EGFR activi ty was necessary for the activation of ERK2, and pharmacological inhibition of ERK2 inhibited the proliferation of Delta EGFR-expressing U87MG cells. Expression of either TC45 or TC45-D182A also suppressed the growth of Delta EGFR-expressing U87MG cells in vivo and prolonged the survival of mice imp lanted intracerebrally with these tumor cells. These results indicate that TC45 can inhibit the Delta EGFR-mediated activation of ERK2 and suppress th e tumorigenicity of Delta EGFR-expressing glioblastoma cells in vivo.