title: Regulation of PTEN inhibition by the pleckstrin homology domain of P-REX2 during insulin signaling and glucose homeostasis.
abstract: 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.
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Cindy
authors.initials: C
authors.lastname: Hodakoski
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Hopkins
authors.forename: Douglas
authors.initials: D
authors.lastname: Barrows
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Mense
authors.forename: Megan
authors.initials: M
authors.lastname: Keniry
authors.forename: Karen E
authors.initials: KE
authors.lastname: Anderson
authors.forename: Philip A
authors.initials: PA
authors.lastname: Kern
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Hawkins
authors.forename: Len R
authors.initials: LR
authors.lastname: Stephens
authors.forename: Ramon
authors.initials: R
authors.lastname: Parsons
mesh_terms: D000818:Animals; D001665:Binding Sites; D001798:Blood Proteins / Q000737:chemistry; D020134:Catalytic Domain; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding
chemical_list: D001798:Blood Proteins; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; C528013:P-Rex2 protein, mouse; C490712:PREX2 protein, human; D010750:Phosphoproteins; C039077:platelet protein P47; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse; D005947:Glucose
keywords: diabetes; metabolism