title: Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 associates with insulin receptor substrate-1 and enhances insulin actions and adipogenesis.
abstract: Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is a unique enzyme that associates with the pSer/Thr-Pro motif and catalyzes cis-trans isomerization. We identified Pin1 in the immunoprecipitates of overexpressed IRS-1 with myc and FLAG tags in mouse livers and confirmed the association between IRS-1 and Pin1 by not only overexpression experiments but also endogenously in the mouse liver. The analysis using deletion- and point-mutated Pin1 and IRS-1 constructs revealed the WW domain located in the N terminus of Pin1 and Ser-434 in the SAIN (Shc and IRS-1 NPXY binding) domain of IRS-1 to be involved in their association. Subsequently, we investigated the role of Pin1 in IRS-1 mediation of insulin signaling. The overexpression of Pin1 in HepG2 cells markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events: phosphatidylinositol 3-kinase binding with IRS-1 and Akt phosphorylation. In contrast, the treatment of HepG2 cells with Pin1 siRNA or the Pin1 inhibitor Juglone suppressed these events. In good agreement with these in vitro data, Pin1 knock-out mice exhibited impaired insulin signaling with glucose intolerance, whereas adenoviral gene transfer of Pin1 into the ob/ob mouse liver mostly normalized insulin signaling and restored glucose tolerance. In addition, it was also demonstrated that Pin1 plays a critical role in adipose differentiation, making Pin1 knock-out mice resistant to diet-induced obesity. Importantly, Pin1 expression was shown to be up-regulated in accordance with nutrient conditions such as food intake or a high-fat diet. Taken together, these observations indicate that Pin1 binds to IRS-1 and thereby markedly enhances insulin action, essential for adipogenesis.
authors: From the Department of Medical Science, Graduate School of Medicine, University of Hiroshima, 1-2-3 Kasumi, Minami-ku, Hiroshima City, Hiroshima 734-8553, Japan.
authors: Yusuke
authors: Y
authors: Nakatsu
authors: Hideyuki
authors: H
authors: Sakoda
authors: Akifumi
authors: A
authors: Kushiyama
authors: Jun
authors: J
authors: Zhang
authors: Hiraku
authors: H
authors: Ono
authors: Midori
authors: M
authors: Fujishiro
authors: Takako
authors: T
authors: Kikuchi
authors: Toshiaki
authors: T
authors: Fukushima
authors: Masayasu
authors: M
authors: Yoneda
authors: Haruya
authors: H
authors: Ohno
authors: Nanao
authors: N
authors: Horike
authors: Machi
authors: M
authors: Kanna
authors: Yoshihiro
authors: Y
authors: Tsuchiya
authors: Hideaki
authors: H
authors: Kamata
authors: Fusanori
authors: F
authors: Nishimura
authors: Toshiaki
authors: T
authors: Isobe
authors: Takehide
authors: T
authors: Ogihara
authors: Hideki
authors: H
authors: Katagiri
authors: Yoshitomo
authors: Y
authors: Oka
authors: Shin-ichiro
authors: S
authors: Takahashi
authors: Hiroki
authors: H
authors: Kurihara
authors: Takafumi
authors: T
authors: Uchida
authors: Tomoichiro
authors: T
authors: Asano
mesh_terms: D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse