title: Par14 protein associates with insulin receptor substrate 1 (IRS-1), thereby enhancing insulin-induced IRS-1 phosphorylation and metabolic actions.
abstract: Pin1 and Par14 are parvulin-type peptidyl-prolyl cis/trans isomerases. Although numerous proteins have been identified as Pin1 substrates, the target proteins of Par14 remain largely unknown. Par14 expression levels are increased in the livers and embryonic fibroblasts of Pin1 KO mice, suggesting a compensatory relationship between the functions of Pin1 and Par14. In this study, the association of Par14 with insulin receptor substrate 1 (IRS-1) was demonstrated in HepG2 cells overexpressing both as well as endogenously in the mouse liver. The analysis using deletion-mutated Par14 and IRS-1 constructs revealed the N-terminal portion containing the basic domain of Par14 and the two relatively C-terminal portions of IRS-1 to be involved in these associations, in contrast to the WW domain of Pin1 and the SAIN domain of IRS-1. Par14 overexpression in HepG2 markedly enhanced insulin-induced IRS-1 phosphorylation and its downstream events, PI3K binding with IRS-1 and Akt phosphorylation. In contrast, treating HepG2 cells with Par14 siRNA suppressed these events. In addition, overexpression of Par14 in the insulin-resistant ob/ob mouse liver by adenoviral transfer significantly improved hyperglycemia with normalization of hepatic PEPCK and G6Pase mRNA levels, and gene suppression of Par14 using shRNA adenovirus significantly exacerbated the glucose intolerance in Pin1 KO mice. Therefore, although Pin1 and Par14 associate with different portions of IRS-1, the prolyl cis/trans isomerization in multiple sites of IRS-1 by these isomerases appears to be critical for efficient insulin receptor-induced IRS-1 phosphorylation. This process is likely to be one of the major mechanisms regulating insulin sensitivity and also constitutes a potential therapeutic target for novel insulin-sensitizing agents.
authors.affiliation: Department of Medical Science, Graduate School of Medicine, University of Hiroshima, 1-2-3 Kasumi, Minami-ku, 734-8553 Hiroshima City, 734-8553 Hiroshima, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakatsu
authors.forename: Takanori
authors.initials: T
authors.lastname: Shinjo
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yamamotoya
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Otani
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Okubo
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kushiyama
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Fukushima
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kamata
authors.forename: Misaki
authors.initials: M
authors.lastname: Iwashita
authors.forename: Fusanori
authors.initials: F
authors.lastname: Nishimura
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Takahashi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Takafumi
authors.initials: T
authors.lastname: Uchida
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018149:Glucose Intolerance / Q000235:genetics; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000628:therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015151:Immunoblotting; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009154:Mutation; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009765:Obesity / Q000097:blood / Q000235:genetics; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference
chemical_list: D007004:Hypoglycemic Agents; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C000606846:PIN1 protein, human; C000606848:PIN4 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse
keywords: Akt; Glucose Metabolism; IRS-1; Insulin; Insulin Signaling; Liver; Par14; Pin1; Signal Transduction