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dc.contributor.author
Slack, Cathy
dc.contributor.author
Werz, Christian
dc.contributor.author
Wieser, Daniela
dc.contributor.author
Alic, Nazif
dc.contributor.author
Foley, Andrea
dc.contributor.author
Stocker, Hugo
dc.contributor.author
Withers, Dominic J.
dc.contributor.author
Thornton, Janet M.
dc.contributor.author
Hafen, Ernst
dc.contributor.author
Partridge, Linda
dc.date.accessioned
2018-10-31T15:02:13Z
dc.date.available
2017-06-08T22:38:27Z
dc.date.available
2018-10-31T15:02:13Z
dc.date.issued
2010-03-19
dc.identifier.issn
1553-7390
dc.identifier.issn
1553-7404
dc.identifier.other
10.1371/journal.pgen.1000881
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/17571
dc.identifier.doi
10.3929/ethz-b-000017571
dc.description.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.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Public Library of Science (PLoS)
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.title
Regulation of Lifespan, Metabolism, and Stress Responses by the Drosophila SH2B Protein, Lnk
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
ethz.journal.title
PLoS Genetics
ethz.journal.volume
6
en_US
ethz.journal.issue
3
en_US
ethz.journal.abbreviated
PLoS Genet
ethz.pages.start
e1000881
en_US
ethz.size
15 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.nebis
005410305
ethz.publication.place
San Francisco, CA
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02538 - Institut für Molekulare Systembiologie / Institute for Molecular Systems Biology::03710 - Hafen, Ernst / Hafen, Ernst
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02030 - Dep. Biologie / Dep. of Biology::02538 - Institut für Molekulare Systembiologie / Institute for Molecular Systems Biology::03710 - Hafen, Ernst / Hafen, Ernst
ethz.date.deposited
2017-06-08T22:38:36Z
ethz.source
ECIT
ethz.identifier.importid
imp59364c7d39b0c99456
ethz.ecitpid
pub:29552
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-18T07:27:09Z
ethz.rosetta.lastUpdated
2018-10-31T15:02:28Z
ethz.rosetta.versionExported
true
ethz.COinS
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