Regulation of the Met Receptor-tyrosine Kinase by the Protein-tyrosine Phosphatase 1B and T-cell Phosphatase
| Autor: | Veena Sangwan, Michel L. Tremblay, Anie Monast, Morag Park, Nadia Dubé, Grigorios N. Paliouras, Jasmine V. Abella |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Phosphatase
Protein tyrosine phosphatase Biology Endoplasmic Reticulum Models Biological Biochemistry Gene Expression Regulation Enzymologic Mice Proto-Oncogene Proteins Animals Humans Protein Isoforms Receptors Growth Factor Phosphorylation Molecular Biology Cell Nucleus Protein Tyrosine Phosphatase Non-Receptor Type 1 Mice Inbred BALB C Protein Tyrosine Phosphatase Non-Receptor Type 2 Kinase Mechanisms of Signal Transduction Cell Biology Proto-Oncogene Proteins c-met Molecular biology Liver Protein kinase domain Hepatocyte Growth Factor Receptor Mutation Signal transduction hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Biological Chemistry. 283:34374-34383 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|