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 GBMs frequently contain amplifications or mutations of the EGFR gene. The most common mutation results in a truncated receptor tyrosine kinase known as Delta EGFR that signals constitutively and promotes GBM growth. Here, we report that the 45-kDa variant of the protein tyrosine phosphatase TCPTP (TC45) can recognize Delta EGFR as a cellular substrate. TC45 dephosphorylated Delta EGFR in U87MG glioblastoma cells and inhibited mitogen-activated protein kinase ERK2 and phosphatidylinositol 3-kinase signaling. In contrast, the substrate-trapping TC45-D182A mutant, which is capable of forming stable complexes with TC45 substrates, suppressed the activation of ERK2 but not phosphatidylinositol 3-kinase. TC45 inhibited the proliferation and anchorage-independent growth of Delta EGFR cells but TC45-D182A only inhibited cellular proliferation. Notably, neither TC45 nor TC45-D182A inhibited the proliferation of U87MG cells that did not express Delta EGFR. Delta EGFR activity 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 implanted intracerebrally with these tumor cells. These results indicate that TC45 can inhibit the Delta EGFR-mediated activation of ERK2 and suppress the tumorigenicity of Delta EGFR-expressing glioblastoma cells in vivo.
Klingler-Hoffmann
M
M
Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
Fodero-Tavoletti
M T
MT
Mishima
K
K
Narita
Y
Y
Cavenee
W K
WK
Furnari
F B
FB
Huang
H J
HJ
Tiganis
T
T
D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002455:Cell Division; D002460:Cell Line; D017931:DNA Primers; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D010766:Phosphorylation; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016019:Survival Analysis
D017931:DNA Primers; D066246:ErbB Receptors; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D017027:Protein Tyrosine Phosphatases; C516653:Ptpn2 protein, mouse