Regulation of the Met Receptor-tyrosine Kinase by the Protein-tyrosine Phosphatase 1B and T-cell PhosphataseS
The non-receptor protein-tyrosine phosphatases (PTPs) 1B and T-cell phosphatase (TCPTP) have been implicated as negative regulators of multiple signaling pathways including receptor-tyrosine kinases. We have identified PTP1B and TCPTP as negative regulators of the hepatocyte growth factor receptor,...
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| Published in: | The Journal of biological chemistry Vol. 283; no. 49; pp. 34374 - 34383 |
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| Main Authors: | , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
American Society for Biochemistry and Molecular Biology
05-12-2008
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | The non-receptor protein-tyrosine phosphatases (PTPs) 1B and T-cell
phosphatase (TCPTP) have been implicated as negative regulators of multiple
signaling pathways including receptor-tyrosine kinases. We have identified
PTP1B and TCPTP as negative regulators of the hepatocyte growth factor
receptor, the Met receptor-tyrosine kinase.
In vivo
, loss of PTP1B or
TCPTP enhances hepatocyte growth factor-mediated phosphorylation of Met. Using
substrate trapping mutants of PTP1B or TCPTP, we have demonstrated that both
phosphatases interact with Met and that these interactions require
phosphorylation of twin tyrosines (Tyr-1234/1235) in the activation loop of
the Met kinase domain. Using confocal microscopy, we show that trapping
mutants of both PTP1B and the endoplasmic reticulum-targeted TCPTP isoform,
TC48, colocalize with Met and that activation of Met enables the
nuclear-localized isoform of TCPTP, TC45, to exit the nucleus. Using small
interfering RNA against PTP1B and TCPTP, we demonstrate that phosphorylation
of Tyr-1234/1235 in the activation loop of the Met receptor is elevated in the
absence of either PTP1B or TCPTP and further elevated upon loss of both
phosphatases. This enhanced phosphorylation of Met corresponds to enhanced
biological activity and cellular invasion. Our data demonstrate that PTP1B and
TCPTP play distinct and non-redundant roles in the regulation of the Met
receptor-tyrosine kinase. |
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| Bibliography: | Holds the Diane and Sal Guerrera Chair in Cancer Genetics at McGill University. To whom correspondence should be addressed: Molecular Oncology Group, McGill University Health Centre, Montréal, Québec H3A 1A1, Canada. Fax: 514-398-6769; E-mail: morag.park@mcgill.ca. Present address: European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, Meyerhofstrasse 1, 69117 Heidelberg, Germany. A Scientist of the Canadian Institutes of Health Research. The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1. This research was supported by a fellowship from Cancer Research Society, Inc. and the Terry Fox Foundation (National Cancer Institute of Canada) (to V. S.), by the McGill University Health Center and Faculty of Medicine, McGill University (to G. P.), by United States Department of Defense Breast Cancer Research Initiative Grant DAMD17-99-1-9284 (to J. A.), and by a Canadian Institutes of Health Research Doctoral Award and Alexander McFee Memorial Fellowship (to N. D.). This work was also supported by the Cancer Research Society, Inc. and Canadian Institutes of Health Research Operating Grant MOP-62887 (to M. L. T.) and by Canadian Institutes of Health Research operating Grant MOP-1154 (to M. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Co-second authors. |
| ISSN: | 0021-9258 1083-351X |
| DOI: | 10.1074/jbc.M805916200 |