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

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

^*Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724; ^†Dana–Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115; and ^‡Departments of Pathology and Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032

Contributed by Michael H. Wigler

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.

Footnotes

↵ § To whom reprint requests should be addressed. e-mail: tonks{at}cshl.org
ABBREVIATIONS:

PTP,

protein tyrosine phosphatase;

PTK,

protein tyrosine kinase;

GST,

glutathione S-transferase;

MBP,

myelin basic protein;

MAP,

mitogen-activated protein;

RCML,

reduced carboxyamidomethylated and maleylated lysozyme