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Regulation of Lifespan, Metabolism, and Stress Responses by the Drosophila SH2B Protein, Lnk

Slack, C; Werz, C; Wieser, D; Alic, N; Foley, A; Stocker, H; Withers, DJ; ... Partridge, L; + view all (2010) Regulation of Lifespan, Metabolism, and Stress Responses by the Drosophila SH2B Protein, Lnk. PLoS Genetics , 6 (3) , Article e1000881. 10.1371/journal.pgen.1000881. Green open access

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Abstract

Drosophila Lnk is the single ancestral orthologue of a highly conserved family of structurally-related intracellular adaptor proteins, the SH2B proteins. As adaptors, they lack catalytic activity but contain several protein-protein interaction domains, thus playing a critical role in signal transduction from receptor tyrosine kinases to form protein networks. Physiological studies of SH2B function in mammals have produced conflicting data. However, a recent study in Drosophila has shown that Lnk is an important regulator of the insulin/insulin-like growth factor (IGF)-1 signaling (IIS) pathway during growth, functioning in parallel to the insulin receptor substrate, Chico. As this pathway also has an evolutionary conserved role in the determination of organism lifespan, we investigated whether Lnk is required for normal lifespan in Drosophila. Phenotypic analysis of mutants for Lnk revealed that loss of Lnk function results in increased lifespan and improved survival under conditions of oxidative stress and starvation. Starvation resistance was found to be associated with increased metabolic stores of carbohydrates and lipids indicative of impaired metabolism. Biochemical and genetic data suggest that Lnk functions in both the IIS and Ras/Mitogen activated protein Kinase (MapK) signaling pathways. Microarray studies support this model, showing transcriptional feedback onto genes in both pathways as well as indicating global changes in both lipid and carbohydrate metabolism. Finally, our data also suggest that Lnk itself may be a direct target of the IIS responsive transcription factor, dFoxo, and that dFoxo may repress Lnk expression. We therefore describe novel functions for a member of the SH2B protein family and provide the first evidence for potential mechanisms of SH2B regulation. Our findings suggest that IIS signaling in Drosophila may require the activity of a second intracellular adaptor, thereby yielding fundamental new insights into the functioning and role of the IIS pathway in ageing and metabolism.

Type: Article
Title: Regulation of Lifespan, Metabolism, and Stress Responses by the Drosophila SH2B Protein, Lnk
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1000881
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1000881
Language: English
Additional information: © 2010 Slack et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: INSULIN-RECEPTOR KINASE, ADAPTER PROTEIN, TYROSINE KINASE, C-CBL, DIETARY RESTRICTION, PDGF RECEPTOR, FAT-BODY, APS, IDENTIFICATION, DOMAIN
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/134782
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