biostudies-literatureHodakoski CNCATS NIH HHSNIDDK NIH HHSNCI NIH HHSNIGMS NIH HHSBiotechnology and Biological Sciences Research Council155-60https://www.ebi.ac.uk/biostudies/studies/S-EPMC3890808biostudies-literatureUnknown111(1)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 densiProceedings of the National Academy of Sciences of the United States of AmericaRegulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis.PMC3890808T32 CA009503GM008224-20R01 CA155117UL1 TR000117S06 GM008224T32 CA009503-22R01 DK71349BBS/E/B/000C0415R01 CA082783R01 DK071349BBS/E/B/000C0413Hopkins BDMense SMKeniry MAnderson KEBarrows DParsons RStephens LRKern PAHodakoski CHawkins PTfalseRegulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis.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 densi2014-01-01T00:00:00Z2014 Jan2026-04-15T11:16:07.865Z2026-04-07T13:56:01.626ZS-EPMC38908082436709010.1073/pnas.1213773111