Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a phosphatase that is frequently altered in cancer. PTEN has phosphatase-dependent and - independent roles; and genetic alterations in PTEN lead to deregulation of protein synthesis, cell cycle, migration, growth, DNA repair, and survival signaling. PTEN localization, stability, conformation, and phosphatase activity are controlled by an array of protein-protein interactions and post-translational modifications. Thus, PTEN-interacting and modifying proteins have profound effects on PTEN’s tumor suppressive functions. Moreover, recent studies identified mechanisms by which PTEN can exit cells, either via exosomal export or secretion, and act on neighboring cells. This review focuses on modes of PTEN protein regulation and ways in which perturbations in this regulation may lead to disease.

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Insulin activation of phosphoinositide 3-kinase (PI3K) signaling regulates glucose homeostasis through the production of phosphatidylinositol 3,4,5-trisphosphate (PIP3). The dual-specificity phosphatase and tensin homolog deleted on chromosome 10 (PTEN) blocks PI3K signaling by dephosphorylating PIP3, and is inhibited through its interaction with phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (P-REX2). The mechanism of inhibition and its physiological significance are not known. Here, we report that P-REX2 interacts with PTEN via two interfaces. The pleckstrin homology (PH) domain of P-REX2 inhibits PTEN by interacting with the catalytic region of PTEN, and the inositol polyphosphate 4-phosphatase domain of P-REX2 provides high-affinity binding to the postsynaptic density-95/Discs large/zona occludens-1-binding domain of PTEN. P-REX2 inhibition of PTEN requires C-terminal phosphorylation of PTEN to release the P-REX2 PH domain from its neighboring diffuse B-cell lymphoma homology domain. Consistent with its function as a PTEN inhibitor, deletion of Prex2 in fibroblasts and mice results in increased Pten activity and decreased insulin signaling in liver and adipose tissue. Prex2 deletion also leads to reduced glucose uptake and insulin resistance. In human adipose tissue, P-REX2 protein expression is decreased and PTEN activity is increased in insulin-resistant human subjects. Taken together, these results indicate a functional role for P-REX2 PH-domain-mediated inhibition of PTEN in regulating insulin sensitivity and glucose homeostasis and suggest that loss of P-REX2 expression may cause insulin resistance.metabolism | diabetes P hosphatases are essential for the regulation of many signal transduction pathways, and altered phosphatase activity disrupts various cellular processes. Phosphatases are divided into two families, the serine (Ser)/threonine (Thr) phosphatases and the tyrosine (Tyr) phosphatases, which include the subfamily of dualspecificity phosphatases (1). Serine/threonine phosphatases are predominantly regulated by the formation of inhibitor complexes (2). Direct phosphorylation of both phosphatases and their inhibitors has also been implicated in serine/threonine phosphatase regulation (2). Protein tyrosine phosphatases (PTPs) are mainly regulated by reversible oxidation of the catalytic pocket (3). However, phosphorylation has also been implicated in their regulation (4).The dual-specificity phosphatase and tensin homolog deleted from chromosome 10 (PTEN) was discovered through the mapping of homozygous deletions in cancer (5, 6). PTEN has the conserved PTP catalytic motif within its phosphatase domain (PD) and a C2 domain, both of which are required to dephosphorylate its primary substrate, phosphatidylinositol 3,4,5-trisphosphate (PIP3). This generates phosphatidylinositol 4,5-bisphosphate. thereby inhibiting PIP3-mediated recruitment and activation of the serine/threonine kinase AKT (7-9). Beyond these domains, the C-terminal tail of PTEN is phosphorylated at Ser-366, Ser-3...