Regulation of insulin signaling in skeletal muscle by PIP3 phosphatase, SKIP, and endoplasmic reticulum molecular chaperone glucose-regulated protein 78

• SKIP formed a complex with GRP78.
• GRP78 binding mediated the localization of SKIP at ER.
• GRP78 was necessary for insulin-induced membrane localization of SKIP.
• GRP78 was necessary for insulin-induced SKIP–Pak1 binding and the subsequent inhibition of insulin signaling.
• GRP78 and SKIP were necessary for the inhibition of insulin signaling in skeletal muscle.

Insulin resistance is characterized as a pathogenic factor in type 2 diabetes. Despite skeletal muscle being primarily responsible for systemic glucose disposal, the mechanisms underlying the induction of insulin resistance in skeletal muscle have not been fully elucidated. A number of studies have shown that it is characterized by the inhibition of the phosphatidylinositol (PI) 3-kinase signaling pathway. Here, we show that skeletal muscle- and kidney-enriched inositol polyphosphate phosphatase (SKIP), a phosphatidylinositol-3,4,5-trisphosphate (PIP3) phosphatase, and glucose-regulated protein 78 (GRP78) are implicated in the inhibition of insulin-dependent PI 3-kinase signaling in skeletal muscle. Mechanistically, under resting conditions, SKIP forms a complex with GRP78 at the endoplasmic reticulum (ER). Insulin stimulation facilitates the dissociation of SKIP from GRP78 and its binding to the activated form of Pak1. GRP78 is necessary for membrane localization and Pak1-binding of SKIP, which facilitates inactivation of the insulin signaling pathway. These findings underscore the specific and prominent role of SKIP and GRP78 in the regulation of insulin-dependent PI 3-kinase signaling in skeletal muscle.