Dataset Information

Drosophila insulin-like peptides DILP2 and DILP5 stimulation global phosphoproteome

ABSTRACT: Insulin and IGF signaling (IIS) is a complex system that controls diverse processes including growth, development, metabolism, stress responses and aging. Drosophila melanogaster IIS is propagated by eight Drosophila insulin-like peptides (DILPs), homologues of both mammalian insulin and IGFs, with various spatiotemporal expression patterns and functions. DILPs 1-7 are thought to act through a single Drosophila insulin/IGF receptor, InR, but it is unclear how the DILPs thereby mediate a range of physiological phenotypes. We determined the distinct cell signaling effects of DILP2 and DILP5 stimulation upon Drosophila S2 cells. DILP2 and DILP5 induced similar transcriptional patterns, but differed in signal transduction kinetics. DILP5 induced sustained phosphorylation of Akt, while DILP2 produced acute, transient Akt phosphorylation. Accordingly, we used phosphoproteomic analysis to identify distinct patterns of non-genomic signaling induced by DILP2 and DILP5. Across all treatments and replicates, 5250 unique phosphopeptides were identified, representing 1575 proteins. Among these peptides, DILP2, but not DILP5, dephosphorylated Ser15 on glycogen phosphorylase (GlyP), and DILP2, but not DILP5, was subsequently shown to repress enzymatic GlyP activity in S2 cells. The functional consequences of this difference were evaluated in adult Drosophila dilp mutants: dilp2 null adults have elevated GlyP enzymatic activity relative to wildtype, while dilp5 mutants have reduced GlyP activity.

OTHER RELATED OMICS DATASETS IN: PRJNA437433

INSTRUMENT(S): Q Exactive

ORGANISM(S): Drosophila Melanogaster Drosophila Melanogaster (fruit Fly)

TISSUE(S): Cell Culture

SUBMITTER: Stephanie Post

LAB HEAD: Marc Tatar

PROVIDER: PXD009240 | Pride | 2018-10-19

REPOSITORIES: Pride

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Publications

Drosophila Insulin-Like Peptides DILP2 and DILP5 Differentially Stimulate Cell Signaling and Glycogen Phosphorylase to Regulate Longevity.

Post Stephanie S Karashchuk Galina G Wade John D JD Sajid Waseem W De Meyts Pierre P Tatar Marc M

Frontiers in endocrinology 20180528

Insulin and IGF signaling (IIS) is a complex system that controls diverse processes including growth, development, metabolism, stress responses, and aging. Drosophila melanogaster IIS is propagated by eight Drosophila insulin-like peptides (DILPs), homologs of both mammalian insulin and IGFs, with various spatiotemporal expression patterns and functions. DILPs 1-7 are thought to act through a single Drosophila insulin/IGF receptor, InR, but it is unclear how the DILPs thereb ...[more]

PMID: 29892262

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Project description: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.

Project description:The nutritional environments that organisms experience are inherently variable, requiring tight coordination of how resources are allocated to different functions relative to the total amount of resources available. A growing body of evidence supports the hypothesis that key endocrine pathways play a fundamental role in this coordination. In particular, the insulin/insulin-like growth factor signaling (IIS) and target of rapamycin (TOR) pathways have been implicated in nutrition-dependent changes in metabolism and nutrient allocation, however little is known about the genetic basis of standing variation in the pathways. To characterize natural genetic variation in the IIS/TOR pathway, we used over 250 recombinant inbred lines (RILs) derived from a multiparental mapping population, the Drosophila Synthetic Population Resource (DSPR), to map QTL for transcript levels of the genes encoding 52 of the core components of the IIS/TOR pathway in three different nutritional environments (dietary restriction, control, and high sugar). In addition, we assayed lifespan for 80 RILs in both dietary restriction and control diets. We identified cis (i.e., local) QTL for six transcripts, all of which are significant in multiple nutrient environments. Further, we identified trans (i.e., distant) QTL for two transcripts, specific to a single nutrient environment, and one “plasticity” QTL that influences the change in gene expression between the control and high sugar diet. Nearly all transcripts, 85%, were significantly differentially expressed between diets. A discriminant function analysis for the control and dietary restriction treatments identified which transcripts best predict the diet treatment. The resulting composite discriminant function scores are correlated with median lifespan (r = 0.45) and mapping these scores revealed a significant QTL within the dietary restriction diet. Our results corroborate the association between the IIS/TOR pathway and the increase in lifespan under dietary restriction in a natural population and identify new locations in the genome involved in regulating the IIS/TOR pathway.

Dataset Information

Drosophila insulin-like peptides DILP2 and DILP5 stimulation global phosphoproteome

Publications

<i>Drosophila</i> Insulin-Like Peptides DILP2 and DILP5 Differentially Stimulate Cell Signaling and Glycogen Phosphorylase to Regulate Longevity.

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