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

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.

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

“…2 PTEN is a phosphatase that has both a lipid 3 and a dualspecificity protein phosphatase activity. 4 Its growth-attenuating activity has mostly been ascribed to the dephosphorylation of plasma membrane-localized phosphatidylinositol 3,4, 5-trisphosphate (PIP3). Through this lipid phosphatase activity, PTEN keeps the levels of PIP3 low and antagonizes the phosphoinositide 3-kinase (PI3K)-Akt pathway.…”

The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells

“…Germ-line mutations of PTEN are the cause of Cowden's and BannayanZonana breast cancer predisposition syndromes, conditions in which 80 per cent of the associated tumors that arise are breast cancers Marsh et al, 1997). PTEN is also required for embryogenesis, but embryonic stem cells lacking functional PTEN have greater tumorigenic capability and heterozygous PTEN`knockout' mice manifest the bowel hamartomas characteristic of Cowden's syndrome as well as an increased propensity for tumor development (Di Cristofano et al, 1998;Suzuki et al, 1998;Podsypanina et al, 1999) PTEN encodes a 403-amino-acid phosphatase capable of dephosphorylating phosphorylated serine, threonine and tyrosine residues (Myers et al, 1997). PTEN interacts with the focal adhesion kinase (FAK) and, by virtue of its protein tyrosine phosphatase activity, PTEN reduces FAK phosphorylation and activity so as to alter cell adhesion, spreading and migration (Tamura et al, 1998.…”

“…Importantly, PTEN also has the ability to dephosphorylate position D3 of phosphatidylinositol (3,4,5) trisphosphate, the latter of which represents a direct product of phosphatidylinositol 3-kinase (PI3K) activity (Maehama and Dixon, 1998). Strikingly, a number of germline and sporadic mutations in PTEN, such as the substitution of glutamic acid for the glycine residue at position 129 (G129E), ablate the ability of PTEN to dephosphorylate phosphatidylinositol (3,4,5) trisphosphate, but leave PTEN protein phosphatase activity intact (Furnari et al, 1998;Myers et al, 1997Myers et al, , 1998. The association of these mutations with cancer, combined with the capacity of the G129E mutated form of PTEN to dephosphorylate FAK and regulate cell spreading in a fashion indistinguishable from wildtype PTEN (Tamura et al, 1998), indicates that dephosphorylation of phosphatidylinositol (3,4,5) trisphosphate represents a function of PTEN critical to this protein's, ability to act as a tumor suppressor.…”

PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein

“…The functions of PTEN as a tumour suppressor appear to be related to its activities as: (i) a dual protein phosphatase (Myers et al, 1997) promoting the inhibition of the focal adhesion kinase (FAK) and the signalling downstream of this molecule Tamura et al, 1998), and (ii) its ability to dephosphorylate phosphatidylinositol 3,4,5 triphosphate (Maehama and Dixon, 1998); thus inhibiting the PI-3K signalling cascade (Li and Sun, 1998;Stambolic et al, 1998;Furnari et al, 1998;Haas-Kogan et al, 1998;Wu et al, 1998). These two pathways converge to modulate speci®c cell processes, in particular the organization of the actin cytoskeleton, in which the e ects of PTEN expression have been recently well established , and also the modulation of the cell cycle progression.…”