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. 1997 Aug 19;94(17):9052-7.
doi: 10.1073/pnas.94.17.9052.

P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase

M P Myers  1 , J P Stolarov, C Eng, J Li, S I Wang, M H Wigler, R Parsons, N K Tonks
Affiliations

P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase

M P Myers et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Figure 1
Figure 1
Tyrosine phosphatase activity of purified P-TEN. (A) P-TEN was tested for protein phosphatase activity using the indicated tyrosine-phosphorylated substrates. Activity is expressed as pmol of phosphate released. A catalytically inactive mutant of P-TEN (P-TENC124S) was included as a control to rule out the possibility of contaminating bacterial phosphatases. (B) Comparison of P-TEN and cdc14 activities. P-TEN and cdc14 were assayed as above with RCML or polyGlu4Tyr1, and the activity is expressed as pmol of phosphate released per min per mg.
Figure 2
Figure 2
Dual-specificity phosphatase activity of purified P-TEN. P-TEN was tested for protein phosphatase activity using the indicated serine/threonine-phosphorylated substrates. Activity is expressed as pmol of phosphate released. A catalytically inactive mutant of P-TEN (P-TENC124S) was included to control for contaminating bacterial phosphatases. Casein was phosphorylated, as indicated, with casein kinase II (CKII) or protein kinase A (PKA).
Figure 3
Figure 3
P-TEN does not dephosphorylate ERK2. Phosphorylated ERK2 was incubated with P-TEN or MKP-1 for the indicated times and ERK2 assayed for residual phosphotyrosine by immunoblotting (A) with an anti-phosphotyrosine antibody or (B) by immunoblotting with anti-MAP kinase antibodies to visualize the change in electrophoretic mobility.
Figure 4
Figure 4
Location of P-TEN mutations. A diagram of P-TEN showing the locations of the point mutations, indicated by an ∗, that were tested in this study. In addition, the predicted structural motifs (see text) in which these mutations lie is also indicated.
Figure 5
Figure 5
Disruption of P-TEN activity by point mutations found in tumor samples. The indicated point mutations were introduced into recombinant P-TEN and their effects on phosphatase activity were determined. Assays were performed with polyGlu4Tyr1 for 15 min. Activity is expressed as pmol of phosphate liberated per min per mg of P-TEN. Assays were performed in triplicate and are expressed as the mean ± SD. The catalytically inactive mutant of P-TEN (P-TENC124S) was included as control to rule out the possibility of contaminating bacterial phosphatases.
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