Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling

SHEPHERD, Peter R.; WITHERS, Dominic J.; SIDDLE, Kenneth

doi:10.1042/bj3330471

Cited by 953PI3K/AKT/mTOR signaling in cancerMetabolism, Diabetes, and CancerProtein Kinase Regulation and GTPase Signaling

Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling

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SHEPHERD, Peter R., WITHERS, Dominic J., SIDDLE, Kenneth·1998·Biochemical Journal

DOI 10.1042/bj3330471PMC PMC1219607

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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.

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PI 3-kinase is activated when the dimer binds to IRS-1.
“PI 3-kinase is activated when the dimer binds to IRS-1 [9].”
From Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor (2005) · cites this paper as [9]
PI 3-kinase is a heterodimer composed of a regulatory subunit (p85α) and a catalytic sub-unit (p110).
“PI 3-kinase is a heterodimer composed of a regulatory subunit (p85α) and a catalytic sub-unit (p110)”
From Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor (2005) · cites this paper as [9]

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Authors: SHEPHERD, P. R., WITHERS, D. J., & SIDDLE, K.
Affiliations: University College London (GB)
Joslin Diabetes Center (US)
University of Cambridge (GB)
ORCID: SHEPHERD, Peter R.
WITHERS, Dominic J.
Venue: Biochemical Journal
Publisher: Portland Press Ltd.
Published: 1998-08-01
Volume: 333
Issue: 3
Pages: 471-490
ISSN: 0264-6021 (ISSN-L)
1470-8728
DOI: 10.1042/bj3330471
PMC: PMC1219607
OpenAlex: W1841050729
Cited by: 953
References: 338
Citations by year: 2026: 5 · 2025: 4 · 2024: 7 · 2023: 13 · 2022: 15 · 2021: 7 · 2020: 22 · 2019: 19 · 2018: 13 · 2017: 16 · 2016: 18 · 2015: 29 · 2014: 21 · 2013: 15 · 2012: 31
FWCI: 6.22
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Biochemical Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
UCL Discovery (University College London) (submittedVersion)
Funders: Medical Research Council
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: phosphatidylinositol 3-kinase, insulin signaling, insulin receptor, phosphoinositide 3-phosphate, pleckstrin homology domain, Akt, allosteric regulation, lipid second messengers, glucose metabolism, lipid metabolism
MeSH terms: Animals, Humans, Insulin, Signal Transduction, Phosphatidylinositol 3-Kinases

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Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling

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