P-Rex2 suppresses glucose uptake into liver and skeletal muscle through different adaptor functions.

ABSTRACT: P-Rex2 is a Rac guanine-nucleotide factor (Rac-GEF) that controls glucose homeostasis. This role is thought to be mediated through its adaptor function inhibiting Pten rather than through its Rac-GEF activity, but this remains to be demonstrated. To examine this question, we have investigated the roles of P-Rex2 in glucose homeostasis using Prex2^-/- and catalytically-inactive Prex2^GD mice. We show that P-Rex2 is required for insulin sensitivity but limits glucose clearance, suppressing glucose uptake into liver and skeletal muscle independently of its catalytic activity. In hepatocytes, P-Rex2 suppresses Glut2 cell surface levels, mitochondrial membrane potential and mitochondrial ATP production. We identify the orphan GPCR Gpr21 as a P-Rex2 target and propose that P-

SUBMITTER: Tsonou E 

PROVIDER: S-EPMC12325715 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature