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.
Highlights
SH2B proteins are a recently identified family of intracellular adaptor proteins that transduce signals downstream of a number of receptor tyrosine kinases (RTKs)
Recent genetic evidence has described a role for the single ancestral SH2B protein in Drosophila (Lnk) during insulin-like growth factor (IGF)-1 signaling (IIS)-mediated growth control
Our results support a model in which Lnk functions as an intracellular adaptor for transduction of the IIS and Ras/ Mitogen activated protein Kinase (MapK) signaling cascades to mediate these physiological processes
Summary
SH2B proteins are a recently identified family of intracellular adaptor proteins that transduce signals downstream of a number of receptor tyrosine kinases (RTKs). Several SH2B family members have been identified in mammals so far including SH2B1 (of which there are four splice variants: SH2B1a, SH2B1b, SH2B1c and SH2B1d), SH2B2 (APS) and SH2B3 (Lnk) They are characterised by a number of conserved domains including a central pleckstrin homology (PH-) domain, a C-terminal Src Homology 2 (SH2-) domain, an Nterminal proline rich region, multiple consensus sites for tyrosine and serine/threonine phosphorylation and a highly conserved C-terminal c-Cbl recognition motif [6,10,11,12]. These domains function as protein-protein interaction motifs and so allow SH2B proteins to integrate and transduce intracellular signals from multiple signaling networks in the absence of intrinsic catalytic activity [6,10,11,12]
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