Phosphoinositide 3-kinase Regulatory Subunit P85alpha Suppresses Insulin Action Via Positive Regulation of PTEN

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Aug 2

PMID 16880400

Citations 82

Authors

Cullen M Taniguchi

Thien T Tran

Tatsuya Kondo

Ji Luo

Kohjiro Ueki

Lewis C Cantley

C Ronald Kahn

Affiliations

Soon will be listed here.

Abstract

The phosphoinositide 3-kinase (PI3K) pathway is central to the metabolic actions of insulin on liver. Here, we show that mice with a liver-specific deletion of the p85alpha regulatory subunit of PI3K (L-Pik3r1KO) exhibit a paradoxical improvement of hepatic and peripheral insulin sensitivity. Although PI3K enzymatic activity is diminished in L-Pik3r1KO livers because of a reduced level of regulatory and catalytic subunits of PI3K, insulin-stimulated Akt activity is actually increased. This increased Akt activity correlates with increased phosphatidylinositol (3,4,5)-trisphosphate levels which are due, at least in part, to diminished activity of the (3,4,5)-trisphosphate phosphatase PTEN. Thus, the regulatory subunit p85alpha is a critical modulator of insulin sensitivity in vivo not only because of its effects on PI3K activation, but also as a regulator of PTEN activity.

Citing Articles

PI3KR1 and AKT1 in largemouth bass (Micropterus salmoides): molecular cloning, characterization, and its involvement in the alleviation of hepatic glycogen deposition caused by insulin inclusion in vitro.

Li Y, Chen S, Liu Y, Liu P, Li S, Liu N Fish Physiol Biochem. 2024; 50(6):2373-2388.

PMID: 39150597 DOI: 10.1007/s10695-024-01379-6.

Divergent roles of the regulatory subunits of class IA PI3K.

Kim C, Lee J, Park S Front Endocrinol (Lausanne). 2024; 14:1152579.

PMID: 38317714 PMC: 10839044. DOI: 10.3389/fendo.2023.1152579.

Molecular Insight into the Pharmacological Potential of Leaf Extract for Type-2 Diabetes Management Using the Network Pharmacology Approach.

Fatimawali , Tallei T, Johnson Kepel B, Bodhi W, Manampiring A, Nainu F Medicina (Kaunas). 2023; 59(11).

PMID: 38003949 PMC: 10673377. DOI: 10.3390/medicina59111899.

The Role of PIK3R1 in Metabolic Function and Insulin Sensitivity.

Tsay A, Wang J Int J Mol Sci. 2023; 24(16).

PMID: 37628845 PMC: 10454413. DOI: 10.3390/ijms241612665.

Insulin Regulation of Hepatic Lipid Homeostasis.

Uehara K, Santoleri D, Garcia Whitlock A, Titchenell P Compr Physiol. 2023; 13(3):4785-4809.

PMID: 37358513 PMC: 10760932. DOI: 10.1002/cphy.c220015.

References

Cai D, Yuan M, Frantz D, Melendez P, Hansen L, Lee J . Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005; 11(2):183-90. PMC: 1440292. DOI: 10.1038/nm1166. View

Taniguchi C, Ueki K, Kahn R . Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J Clin Invest. 2005; 115(3):718-27. PMC: 548317. DOI: 10.1172/JCI23187. View

Bandyopadhyay G, Yu J, Ofrecio J, Olefsky J . Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes. 2005; 54(8):2351-9. DOI: 10.2337/diabetes.54.8.2351. View

Virkamaki A, Ueki K, Kahn C . Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest. 1999; 103(7):931-43. PMC: 408269. DOI: 10.1172/JCI6609. View

Backer J, Myers Jr M, Shoelson S, Chin D, Sun X, Miralpeix M . Phosphatidylinositol 3'-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J. 1992; 11(9):3469-79. PMC: 556882. DOI: 10.1002/j.1460-2075.1992.tb05426.x. View

Luo J, McMullen J, Sobkiw C, Zhang L, Dorfman A, Sherwood M . Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy. Mol Cell Biol. 2005; 25(21):9491-502. PMC: 1265829. DOI: 10.1128/MCB.25.21.9491-9502.2005. View

Taniguchi C, Kondo T, Sajan M, Luo J, Bronson R, Asano T . Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab. 2006; 3(5):343-53. DOI: 10.1016/j.cmet.2006.04.005. View

Cherrington A . The role of hepatic insulin receptors in the regulation of glucose production. J Clin Invest. 2005; 115(5):1136-9. PMC: 1087191. DOI: 10.1172/JCI25152. View

Mauvais-Jarvis F, Ueki K, Fruman D, Hirshman M, Sakamoto K, Goodyear L . Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J Clin Invest. 2002; 109(1):141-9. PMC: 150818. DOI: 10.1172/JCI13305. View

10.

Lam T, Pocai A, Gutierrez-Juarez R, Obici S, Bryan J, Aguilar-Bryan L . Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med. 2005; 11(3):320-7. DOI: 10.1038/nm1201. View

11.

Ueki K, Fruman D, Brachmann S, Tseng Y, Cantley L, Kahn C . Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol Cell Biol. 2002; 22(3):965-77. PMC: 133541. DOI: 10.1128/MCB.22.3.965-977.2002. View

12.

Saltiel A, Kahn C . Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414(6865):799-806. DOI: 10.1038/414799a. View

13.

Fisher S, Kahn C . Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production. J Clin Invest. 2003; 111(4):463-8. PMC: 151923. DOI: 10.1172/JCI16426. View

14.

Cantley L, Neel B . New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A. 1999; 96(8):4240-5. PMC: 33561. DOI: 10.1073/pnas.96.8.4240. View

15.

Terauchi Y, Tsuji Y, Satoh S, Minoura H, Murakami K, Okuno A . Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet. 1999; 21(2):230-5. DOI: 10.1038/6023. View

16.

Barbour L, Shao J, Qiao L, Leitner W, Anderson M, Friedman J . Human placental growth hormone increases expression of the p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle. Endocrinology. 2003; 145(3):1144-50. DOI: 10.1210/en.2003-1297. View

17.

Shimomura I, Matsuda M, Hammer R, Bashmakov Y, Brown M, Goldstein J . Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell. 2000; 6(1):77-86. View

18.

Chen D, Mauvais-Jarvis F, Bluher M, Fisher S, Jozsi A, Goodyear L . p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. Mol Cell Biol. 2003; 24(1):320-9. PMC: 303335. DOI: 10.1128/MCB.24.1.320-329.2004. View

19.

Postic C, Magnuson M . DNA excision in liver by an albumin-Cre transgene occurs progressively with age. Genesis. 2000; 26(2):149-50. DOI: 10.1002/(sici)1526-968x(200002)26:2<149::aid-gene16>3.0.co;2-v. View

20.

Luo J, Field S, Lee J, Engelman J, Cantley L . The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. J Cell Biol. 2005; 170(3):455-64. PMC: 2171479. DOI: 10.1083/jcb.200503088. View