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A protein tyrosine phosphatase activity associated with the hepatocyte growth factor/scatter factor receptor
E Villa-Moruzzi1, S Lapi, M Prat
1Department of Experimental Biomedicine, University of Pisa, Italy.
Abstract:
The receptor for the growth and motility factor, hepatocyte growth factor/scatter factor (HGF/SF), is a transmembrane tyrosine kinase encoded by the MET oncogene. Previous work has shown that receptor phosphorylation on tyrosine is critical for both kinase activation and association with intracellular signal transducers. In this paper, we report that a protein tyrosine phosphatase activity (PTP) coprecipitates with the HGF/SF receptor. The associated PTP activity correlates with the kinase activation of the receptor, increasing up to 5-fold over the basal level after HGF/SF stimulation. The increase is reversible and time- and dose-dependent. A comparable level of activity is associated with constitutively tyrosine-phosphorylated receptors immunoprecipitated from cells where the MET oncogene is amplified and overexpressed. In these cells, a parallel decrease in PTP activity is observed after inhibition of receptor tyrosine phosphorylation following protein kinase C activation. The associated PTP activity is effective in dephosphorylating the HGF/SF receptor. These data show that a protein tyrosine phosphatase is functionally coupled to the HGF/SF receptor.
Insights
A newly discovered protein tyrosine phosphatase (PTP) activity is linked to the hepatocyte growth factor/scatter factor (HGF/SF) receptor. This PTP dephosphorylates the receptor, suggesting a role in regulating HGF/SF signaling pathways.
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncogenesis
Background:
- The MET oncogene encodes the receptor for hepatocyte growth factor/scatter factor (HGF/SF), a transmembrane tyrosine kinase crucial for cell growth and motility.
- Receptor tyrosine phosphorylation is essential for HGF/SF receptor kinase activation and downstream signaling.
- The precise regulation of HGF/SF receptor phosphorylation status is critical for cellular processes.
Purpose of the Study:
- To investigate the presence and function of associated enzymatic activities with the HGF/SF receptor.
- To determine if protein tyrosine phosphatase (PTP) activity is associated with the HGF/SF receptor.
- To elucidate the functional relationship between PTP activity and HGF/SF receptor phosphorylation.
Main Methods:
- Co-precipitation assays to detect associated enzymatic activities with the HGF/SF receptor.
- Measurement of tyrosine phosphatase activity in immunoprecipitated HGF/SF receptor complexes.
- Analysis of receptor phosphorylation status and PTP activity in response to HGF/SF stimulation and under conditions of MET oncogene amplification.
Main Results:
- A protein tyrosine phosphatase (PTP) activity was found to co-precipitate with the HGF/SF receptor.
- Associated PTP activity increased up to 5-fold upon HGF/SF stimulation, demonstrating a correlation with receptor kinase activation.
- The associated PTP activity was capable of dephosphorylating the HGF/SF receptor, indicating a direct functional role.
Conclusions:
- A protein tyrosine phosphatase is functionally coupled to the HGF/SF receptor.
- This PTP activity plays a role in regulating the phosphorylation state of the HGF/SF receptor.
- The findings suggest a novel regulatory mechanism for HGF/SF signaling involving receptor-associated PTP.