Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk

Cathy Slack, Christian Werz, Daniela Wieser, Nazif Alic, Andrea Foley, Hugo Stocker, Dominic J. Withers, Janet M. Thornton, Ernst Hafen, Linda Partridge

Research output: Contribution to journalArticle

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.

LanguageEnglish
Article numbere1000881
Number of pages15
JournalPLoS Genetics
Volume6
Issue number3
DOIs
Publication statusPublished - 19 Mar 2010

Fingerprint

Drosophila
stress response
metabolism
protein
Starvation
starvation
Proteins
proteins
Protein Interaction Domains and Motifs
Insulin Receptor
Carbohydrate Metabolism
somatomedins
Receptor Protein-Tyrosine Kinases
protein-protein interactions
Somatomedins
carbohydrate metabolism
global change
Mitogen-Activated Protein Kinases
mitogen-activated protein kinase
Lipid Metabolism

Bibliographical note

© 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.

Cite this

Slack, C., Werz, C., Wieser, D., Alic, N., Foley, A., Stocker, H., ... Partridge, L. (2010). Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk. PLoS Genetics, 6(3), [e1000881]. https://doi.org/10.1371/journal.pgen.1000881
Slack, Cathy ; Werz, Christian ; Wieser, Daniela ; Alic, Nazif ; Foley, Andrea ; Stocker, Hugo ; Withers, Dominic J. ; Thornton, Janet M. ; Hafen, Ernst ; Partridge, Linda. / Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk. In: PLoS Genetics. 2010 ; Vol. 6, No. 3.
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Slack, C, Werz, C, Wieser, D, Alic, N, Foley, A, Stocker, H, Withers, DJ, Thornton, JM, Hafen, E & Partridge, L 2010, 'Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk' PLoS Genetics, vol. 6, no. 3, e1000881. https://doi.org/10.1371/journal.pgen.1000881

Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk. / Slack, Cathy; Werz, Christian; Wieser, Daniela; Alic, Nazif; Foley, Andrea; Stocker, Hugo; Withers, Dominic J.; Thornton, Janet M.; Hafen, Ernst; Partridge, Linda.

In: PLoS Genetics, Vol. 6, No. 3, e1000881, 19.03.2010.

Research output: Contribution to journalArticle

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T1 - Regulation of lifespan, metabolism, and stress responses by the Drosophila SH2B protein, Lnk

AU - Slack, Cathy

AU - Werz, Christian

AU - Wieser, Daniela

AU - Alic, Nazif

AU - Foley, Andrea

AU - Stocker, Hugo

AU - Withers, Dominic J.

AU - Thornton, Janet M.

AU - Hafen, Ernst

AU - Partridge, Linda

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Y1 - 2010/3/19

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