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P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase
M P Myers1, J P Stolarov, C Eng
1Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Abstract:
Protein tyrosine phosphatases (PTPs) have long been thought to play a role in tumor suppression due to their ability to antagonize the growth promoting protein tyrosine kinases. Recently, a candidate tumor suppressor from 10q23, termed P-TEN, was isolated, and sequence homology was demonstrated with members of the PTP family, as well as the cytoskeletal protein tensin. Here we show that recombinant P-TEN dephosphorylated protein and peptide substrates phosphorylated on serine, threonine, and tyrosine residues, indicating that P-TEN is a dual-specificity phosphatase. In addition, P-TEN exhibited a high degree of substrate specificity, showing selectivity for extremely acidic substrates in vitro. Furthermore, we demonstrate that mutations in P-TEN, identified from primary tumors, tumor cells lines, and a patient with Bannayan-Zonana syndrome, resulted in the ablation of phosphatase activity, demonstrating that enzymatic activity of P-TEN is necessary for its ability to function as a tumor suppressor.
Insights
The tumor suppressor P-TEN is a dual-specificity phosphatase. Its enzymatic activity is crucial for tumor suppression, as mutations leading to loss of function were identified in various cancers and Bannayan-Zonana syndrome.
Area of Science:
- Molecular Biology
- Biochemistry
- Oncology
Background:
- Protein tyrosine phosphatases (PTPs) are implicated in tumor suppression by counteracting protein tyrosine kinases.
- A candidate tumor suppressor, P-TEN, was identified and shows homology to PTPs and tensin.
Purpose of the Study:
- To characterize the enzymatic activity and substrate specificity of P-TEN.
- To investigate the role of P-TEN's enzymatic activity in tumor suppression.
Main Methods:
- Recombinant P-TEN was used to dephosphorylate various substrates.
- Substrate specificity was assessed using protein and peptide substrates.
- Mutations in P-TEN from tumors and Bannayan-Zonana syndrome patients were analyzed.
Main Results:
- Recombinant P-TEN demonstrated dual-specificity phosphatase activity, dephosphorylating serine, threonine, and tyrosine residues.
- P-TEN exhibited high substrate specificity, preferring acidic substrates in vitro.
- Identified mutations in P-TEN from tumors and Bannayan-Zonana syndrome ablated phosphatase activity.
Conclusions:
- P-TEN functions as a dual-specificity phosphatase with specific substrate requirements.
- The enzymatic activity of P-TEN is essential for its tumor suppressor function.