Par14 protein associates with insulin receptor substrate 1 (IRS-1), thereby enhancing insulin-induced IRS-1 phosphorylation and metabolic actions

Autor: Zhang, J., Nakatsu, Y., Shinjo, T., Guo, Y., Sakoda, H., Yamamotoya, T., Otani, Y., Okubo, H., Kushiyama, A., Fujishiro, M., Fukushima, Toshiaki, Tsuchiya, Y., Kamata, H., Iwashita, M., Nishimura, F., Katagiri, H., Takahashi, S., Kurihara, H., Uchida, T., Asano, T.
Jazyk: angličtina
Rok vydání: 2013
Předmět:
medicine.medical_treatment
Obesity/blood/genetics
Mice
Obese
Biochemistry
Binding Sites/genetics
Glucose Intolerance/genetics
Insulin/*pharmacology
Phosphatidylinositol 3-Kinases
Mice
Proto-Oncogene Proteins c-akt/metabolism
Insulin
Phosphorylation
Mice
Knockout
Insulin Receptor Substrate Proteins/genetics/*metabolism
Peptidylprolyl Isomerase/genetics/*metabolism
Phosphorylation/drug effects
Hep G2 Cells
Peptidylprolyl Isomerase
Hyperglycemia/genetics/therapy
Liver
RNA Interference
Signal transduction
Phosphatidylinositol 3-Kinases/metabolism
Protein Binding
Liver/metabolism
medicine.medical_specialty
Insulin Receptor Substrate Proteins
Proto-Oncogene Proteins c-akt
Immunoblotting
Biology
Hypoglycemic Agents/pharmacology
Internal medicine
Glucose Intolerance
medicine
Hypoglycemic Agents
Animals
Humans
Obesity
Molecular Biology
Protein kinase B
Binding Sites
Cell Biology
IRS1
NIMA-Interacting Peptidylprolyl Isomerase
Mice
Inbred C57BL
Insulin receptor
Endocrinology
Metabolism
HEK293 Cells
Hyperglycemia
Mutation
biology.protein
Zdroj: J Biol Chem. 288(No. 28):20692-701
Popis: 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. Background: Par14 is a parvulin-type peptidyl-prolyl cis/trans isomerase homologous with Pin1, but its functions remain largely unknown. Results: Par14 markedly enhanced insulin signaling by associating with IRS-1, and hepatic overexpression of Par14 normalized hyperglycemia in diabetic mice. Conclusion: Par14 exhibits an insulin-sensitizing effect. Significance: This is the first report showing the roles of Par14 in metabolism and signal transduction.
Databáze: OpenAIRE
Externí odkaz: