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https://hdl.handle.net/2440/34741
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Type: | Journal article |
Title: | The protein tyrosine phosphatase TCPTP suppresses the tumorigenicity of glioblastoma cells expressing a mutant epidermal growth factor receptor |
Author: | Klingler-Hoffmann, M. Fodero-Tavoletti, M. Mishima, K. Narita, Y. Cavenee, W. Furnari, F. Huang, H. Tiganis, T. |
Citation: | Journal of Biological Chemistry, 2001; 276(49):46313-46318 |
Publisher: | Amer Soc Biochemistry Molecular Biology Inc |
Issue Date: | 2001 |
ISSN: | 0021-9258 1083-351X |
Statement of Responsibility: | Manuela Klingler-Hoffmann, Michelle T. Fodero-Tavoletti, Kazuhiko Mishima, Yoshitaka Narita, Webster K. Cavenee, Frank B. Furnari, H.-J. Su Huang, and Tony Tiganis |
Abstract: | 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 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 EGFR as a cellular substrate. TC45 dephosphorylated 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 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 EGFR. EGFR activity was necessary for the activation of ERK2, and pharmacological inhibition of ERK2 inhibited the proliferation of EGFR-expressing U87MG cells. Expression of either TC45 or TC45-D182A also suppressed the growth of 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 EGFR-mediated activation of ERK2 and suppress the tumorigenicity of EGFR-expressing glioblastoma cells in vivo. |
Keywords: | Cell Line Animals Mice, Inbred BALB C Humans Mice Glioblastoma Brain Neoplasms DNA Primers Flow Cytometry Survival Analysis Signal Transduction Cell Division Base Sequence Phosphorylation Mutation Female Protein Tyrosine Phosphatases Protein Tyrosine Phosphatase, Non-Receptor Type 2 ErbB Receptors |
Rights: | © 2001 by the American Society for Biochemistry and Molecular Biology. |
DOI: | 10.1074/jbc.M106571200 |
Published version: | http://www.jbc.org/cgi/content/abstract/276/49/46313 |
Appears in Collections: | Aurora harvest 6 Molecular and Biomedical Science publications |
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