PI3K is the dominant signalling pathway recruited by IRS proteins to mediate their effects on metabolism and growth.
6 affiliations
- 1Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK; MRC Laboratory of Medical Sciences, Du Cane Road, London, W12 0NN, UK. Electronic address: [email protected].
- 2MRC Laboratory of Medical Sciences, Du Cane Road, London, W12 0NN, UK.
- 3Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London, SE1 9RT, UK.
- 4The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK; MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
- 5Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, Gower Street, London, WC1E 6BT, UK.
- 6MRC Laboratory of Medical Sciences, Du Cane Road, London, W12 0NN, UK; Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK. Electronic address: [email protected].
Abstract
Objectives
Insulin and Igf1 have pleiotropic effects on development, growth and metabolism. The activated insulin and IGF1 receptors engage insulin receptor substrate (IRS) proteins, intracellular adaptor molecules that recruit multiple downstream signalling pathways, including PI3K and GRB2-RAS-MAPK. Global deletion of IRS1 or IRS2 in mice results in divergent effects on growth, metabolism, and ageing. However, the precise signalling pathways recruited by IRS1 or IRS2 to mediate their physiological effects in vivo have not been defined.Methods
We generated knock-in mice in which either IRS1 or IRS2 was mutated to prevent downstream recruitment of PI3K or GRB2 and undertook phenotypic analysis of these animals.Results
Knock-in mice unable to recruit PI3K to IRS1 (Irs1YnF) or to IRS2 (Irs2YnF) had limited or no compensation in IRS2 and IRS1 signalling respectively. Irs1YnF mice were growth restricted, with reduced adiposity and insulin resistance, but did not develop diabetes due to compensatory increase in β-cell mass. Irs2YnF mice were obese and insulin resistant and developed diabetes due to β-cell failure. In contrast knock-in mice unable to recruit GRB2 to IRS1 (Irs1Y891F) or to IRS2 (Irs2Y911F) displayed normal growth and metabolism.Conclusions
PI3K recruitment by either IRS1 or IRS2 is the primary signalling mediator of the effects of these adaptor molecules on growth and metabolism in mice, and suggest that the other signalling pathways recruited by IRS1 and IRS2, including GRB2, have minimal or redundant roles.
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BibTeX
@article{millership2026pi3k,
title = {{PI3K is the dominant signalling pathway recruited by IRS proteins to mediate their effects on metabolism and growth.}},
author = {Steven J Millership and Nadia Tyler-Rubinstein and Elaine E Irvine and Marika Charalambous and Agharul I Choudhury and Santiago Vernia and Peter Voshol and Antonio Vidal-Puig and Lazaros C Foukas and Dominic J Withers},
journal = {Molecular metabolism},
year = {2026},
month = oct,
doi = {10.1016/j.molmet.2026.102450},
url = {https://europepmc.org/article/MED/42838449},
note = {CC BY},
}
RIS
TY - JOUR
TI - PI3K is the dominant signalling pathway recruited by IRS proteins to mediate their effects on metabolism and growth.
AU - Steven J Millership
AU - Nadia Tyler-Rubinstein
AU - Elaine E Irvine
AU - Marika Charalambous
AU - Agharul I Choudhury
AU - Santiago Vernia
AU - Peter Voshol
AU - Antonio Vidal-Puig
AU - Lazaros C Foukas
AU - Dominic J Withers
PY - 2026
DA - 2026/10/06
JO - Molecular metabolism
DO - 10.1016/j.molmet.2026.102450
UR - https://europepmc.org/article/MED/42838449
AB - Objectives Insulin and Igf1 have pleiotropic effects on development, growth and metabolism. The activated insulin and IGF1 receptors engage insulin receptor substrate (IRS) proteins, intracellular adaptor molecules that recruit multiple downstream signalling pathways, including PI3K and GRB2-RAS-MAPK. Global deletion of IRS1 or IRS2 in mice results in divergent effects on growth, metabolism, and ageing. However, the precise signalling pathways recruited by IRS1 or IRS2 to mediate their physiological effects in vivo have not been defined.Methods We generated knock-in mice in which either IRS1 or IRS2 was mutated to prevent downstream recruitment of PI3K or GRB2 and undertook phenotypic analysis of these animals.Results Knock-in mice unable to recruit PI3K to IRS1 (Irs1YnF) or to IRS2 (Irs2YnF) had limited or no compensation in IRS2 and IRS1 signalling respectively. Irs1YnF mice were growth restricted, with reduced adiposity and insulin resistance, but did not develop diabetes due to compensatory increase in β-cell mass. Irs2YnF mice were obese and insulin resistant and developed diabetes due to β-cell failure. In contrast knock-in mice unable to recruit GRB2 to IRS1 (Irs1Y891F) or to IRS2 (Irs2Y911F) displayed normal growth and metabolism.Conclusions PI3K recruitment by either IRS1 or IRS2 is the primary signalling mediator of the effects of these adaptor molecules on growth and metabolism in mice, and suggest that the other signalling pathways recruited by IRS1 and IRS2, including GRB2, have minimal or redundant roles.
SN - 2212-8778
ER -