Phosphoinositide 3-kinase: the Key Switch Mechanism in Insulin Signalling

Overview

Journal Biochem J

Specialty Biochemistry

Date 1998 Jul 25

PMID 9677303

Citations 205

Authors

P R Shepherd

D J Withers

K Siddle

Affiliations

Soon will be listed here.

Abstract

Insulin plays a key role in regulating a wide range of cellular processes. However, until recently little was known about the signalling pathways that are involved in linking the insulin receptor with downstream responses. It is now apparent that the activation of class 1a phosphoinositide 3-kinase (PI 3-kinase) is necessary and in some cases sufficient to elicit many of insulin's effects on glucose and lipid metabolism. The lipid products of PI 3-kinase act as both membrane anchors and allosteric regulators, serving to localize and activate downstream enzymes and their protein substrates. One of the major ways these lipid products of PI 3-kinase act in insulin signalling is by binding to pleckstrin homology (PH) domains of phosphoinositide-dependent protein kinase (PDK) and protein kinase B (PKB) and in the process regulating the phosphorylation of PKB by PDK. Using mechanisms such as this, PI 3-kinase is able to act as a molecular switch to regulate the activity of serine/threonine-specific kinase cascades important in mediating insulin's effects on endpoint responses.

Citing Articles

MicroRNA, Myostatin, and Metabolic Rate Depression: Skeletal Muscle Atrophy Resistance in Hibernating .

Ingelson-Filpula W, Breedon S, Storey K Cells. 2025; 13(24.

PMID: 39768165 PMC: 11674624. DOI: 10.3390/cells13242074.

Endothelial Dysfunction in Obesity and Therapeutic Targets.

Engin A Adv Exp Med Biol. 2024; 1460:489-538.

PMID: 39287863 DOI: 10.1007/978-3-031-63657-8_17.

Subunit-Specific Developmental Roles of PI3K in SF1-Expressing Cells.

Huynh M, Lyoo S, Yang D, Choi Y, Kim K Endocrinol Metab (Seoul). 2024; 39(5):793-802.

PMID: 39212037 PMC: 11525698. DOI: 10.3803/EnM.2024.1999.

CREB3 suppresses hepatocellular carcinoma progression by depressing AKT signaling through competitively binding with insulin receptor and transcriptionally activating RNA-binding motif protein 38.

He Y, Han S, Li H, Wu Y, Jia W, Chen Z MedComm (2020). 2024; 5(7):e633.

PMID: 38952575 PMC: 11215284. DOI: 10.1002/mco2.633.

Polyploidy and mTOR signaling: a possible molecular link.

Choudhury D, Ghosh D, Mondal M, Singha D, Pothuraju R, Malakar P Cell Commun Signal. 2024; 22(1):196.

PMID: 38539200 PMC: 10976710. DOI: 10.1186/s12964-024-01526-9.

References

Muslin A, Tanner J, Allen P, Shaw A . Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell. 1996; 84(6):889-97. DOI: 10.1016/s0092-8674(00)81067-3. View

Fujita N, Kaku K, Okubo M, Nagasaka Y, Kaneko T . Insulin stimulates protein synthesis of glycogen synthase in rat hepatoma H4 cells associated with acceleration of translation rate. Endocr J. 1996; 43(3):313-20. DOI: 10.1507/endocrj.43.313. View

Burgering B, Coffer P . Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature. 1995; 376(6541):599-602. DOI: 10.1038/376599a0. View

Ridderstrale M, Degerman E, Tornqvist H . Growth hormone stimulates the tyrosine phosphorylation of the insulin receptor substrate-1 and its association with phosphatidylinositol 3-kinase in primary adipocytes. J Biol Chem. 1995; 270(8):3471-4. DOI: 10.1074/jbc.270.8.3471. View

Hemati N, Ross S, Erickson R, Groblewski G, MacDougald O . Signaling pathways through which insulin regulates CCAAT/enhancer binding protein alpha (C/EBPalpha) phosphorylation and gene expression in 3T3-L1 adipocytes. Correlation with GLUT4 gene expression. J Biol Chem. 1997; 272(41):25913-9. DOI: 10.1074/jbc.272.41.25913. View

Vanhaesebroeck B, Welham M, Kotani K, Stein R, Warne P, Zvelebil M . P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A. 1997; 94(9):4330-5. PMC: 20722. DOI: 10.1073/pnas.94.9.4330. View

Venkateswarlu K, Oatey P, Tavare J, Cullen P . Insulin-dependent translocation of ARNO to the plasma membrane of adipocytes requires phosphatidylinositol 3-kinase. Curr Biol. 1998; 8(8):463-6. DOI: 10.1016/s0960-9822(98)70181-2. View

Okada T, Kawano Y, Sakakibara T, Hazeki O, Ui M . Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. J Biol Chem. 1994; 269(5):3568-73. View

Inukai K, Anai M, van Breda E, Hosaka T, Katagiri H, Funaki M . A novel 55-kDa regulatory subunit for phosphatidylinositol 3-kinase structurally similar to p55PIK Is generated by alternative splicing of the p85alpha gene. J Biol Chem. 1996; 271(10):5317-20. DOI: 10.1074/jbc.271.10.5317. View

10.

Levy-Toledano R, Taouis M, Blaettler D, Gorden P, Taylor S . Insulin-induced activation of phosphatidyl inositol 3-kinase. Demonstration that the p85 subunit binds directly to the COOH terminus of the insulin receptor in intact cells. J Biol Chem. 1994; 269(49):31178-82. View

11.

Alessi D, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P . Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996; 15(23):6541-51. PMC: 452479. View

12.

Tanti J, Gremeaux T, Van Obberghen E, Le Marchand-Brustel Y . Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling. J Biol Chem. 1994; 269(8):6051-7. View

13.

Yuan Z, Utsugisawa T, Huang Y, Ishiko T, Nakada S, Kharbanda S . Inhibition of phosphatidylinositol 3-kinase by c-Abl in the genotoxic stress response. J Biol Chem. 1997; 272(38):23485-8. DOI: 10.1074/jbc.272.38.23485. View

14.

Wolf G, Trub T, Ottinger E, Groninga L, Lynch A, White M . PTB domains of IRS-1 and Shc have distinct but overlapping binding specificities. J Biol Chem. 1995; 270(46):27407-10. DOI: 10.1074/jbc.270.46.27407. View

15.

Endemann G, Yonezawa K, Roth R . Phosphatidylinositol kinase or an associated protein is a substrate for the insulin receptor tyrosine kinase. J Biol Chem. 1990; 265(1):396-400. View

16.

Murata K, Wu J, Brautigan D . B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc Natl Acad Sci U S A. 1997; 94(20):10624-9. PMC: 23426. DOI: 10.1073/pnas.94.20.10624. View

17.

Rickles R, Botfield M, Weng Z, Taylor J, Green O, Brugge J . Identification of Src, Fyn, Lyn, PI3K and Abl SH3 domain ligands using phage display libraries. EMBO J. 1994; 13(23):5598-604. PMC: 395523. DOI: 10.1002/j.1460-2075.1994.tb06897.x. View

18.

Ricort J, Tanti J, Van Obberghen E, Le Marchand-Brustel Y . Different effects of insulin and platelet-derived growth factor on phosphatidylinositol 3-kinase at the subcellular level in 3T3-L1 adipocytes. A possible explanation for their specific effects on glucose transport. Eur J Biochem. 1996; 239(1):17-22. DOI: 10.1111/j.1432-1033.1996.0017u.x. View

19.

James S, Downes C, GIGG R, Grove S, Holmes A, Alessi D . Specific binding of the Akt-1 protein kinase to phosphatidylinositol 3,4,5-trisphosphate without subsequent activation. Biochem J. 1996; 315 ( Pt 3):709-13. PMC: 1217264. DOI: 10.1042/bj3150709. View

20.

Rameh L, Arvidsson A, Carraway 3rd K, Couvillon A, Rathbun G, Crompton A . A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains. J Biol Chem. 1997; 272(35):22059-66. DOI: 10.1074/jbc.272.35.22059. View