title: Regulation of insulin signaling in skeletal muscle by PIP3 phosphatase, SKIP, and endoplasmic reticulum molecular chaperone glucose-regulated protein 78.
abstract: 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.
authors.affiliation: Division of Biochemistry, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan. Electronic address: tijuin@med.kobe-u.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ijuin
authors.affiliation: The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Hatano
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hosooka
authors.affiliation: Division of Membrane Biology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
authors.forename: Tadaomi
authors.initials: T
authors.lastname: Takenawa
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation; D006360:Heat-Shock Proteins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D014157:Transcription Factors; C051684:GRP78 protein, rat; C000717248:Hspa5 protein, mouse; C581694:SKIP protein, rat; C531212:Pps protein, mouse; C096024:phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase
keywords: Glucose-regulated protein 78; Insulin; PI 3-kinase; Phosphatidylinositol-3,4,5-trisphosphate; SKIP; Skeletal muscle