The Lnk/SH2B adaptor provides a fail-safe mechanism to establish the Insulin receptor-Chico interaction
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RESEARCH
Open Access
The Lnk/SH2B adaptor provides a fail-safe mechanism to establish the Insulin receptor-Chico interaction Isabel Almudi1,2, Ingrid Poernbacher1,3, Ernst Hafen1 and Hugo Stocker1*
Abstract Background: Insulin/insulin-like growth factor signalling (IIS) has been described as one of the major pathways involved in growth control and homeostasis in multicellular organisms. Whereas its core components are well established, less is known about the molecular functions of IIS regulators. The adaptor molecule Lnk/SH2B has been implicated in IIS but the mechanism by which it promotes IIS activity has remained enigmatic. Results: In this study, we analyse genetic and physical interactions among InR, Chico and Lnk in Drosophila tissues. FRET analysis reveals in vivo binding between all three molecules. Genetically, Lnk acts upstream of Chico. We demonstrate that Chico’s plasma membrane localisation is ensured by both its PH domain and by the interaction with Lnk. Furthermore, Lnk is able to recruit an intracellular InR fragment to the membrane. Conclusions: Thus, by acting as a scaffolding molecule that ensures InR and Chico enrichment at the membrane, Lnk provides a fail-safe mechanism for IIS activation.
Background The Insulin/insulin-like growth factor signalling (IIS) pathway has emerged in the last decade as one of the major signalling pathways involved in the control of growth, body size and homeostasis in multicellular organisms [1-4]. The main intracellular components of IIS in Drosophila are Chico, the homologue of the Insulin Receptor Substrates (IRS), the lipid kinase phosphoinositide 3-kinase (PI3K), the lipid phosphatase PTEN and the serinethreonine kinase dAkt/PKB [5-10]. These intracellular signalling components need to be recruited to the cortical membrane to regulate signalling activity [5,7,11-13]. In addition to the core components, regulators such as Susi [14], Steppke [15] and Lnk [16,17] modulate IIS activity. The Lnk adaptor protein has been identified in an unbiased screen as a component of the pathway based on the reduced body size and lipid accumulation observed in lnk mutant flies [17]. Mutations in the lnk locus were able to rescue the overgrowth phenotype * Correspondence: [email protected] 1 Institute of Molecular Systems Biology, ETH Zürich, Wolfgang-Pauli-Strasse 16, Zürich 8093, Switzerland Full list of author information is available at the end of the article
caused by overexpression of InR, but not to suppress the overgrowth promoted by high activity of PI3K, suggesting that Lnk acts between InR and PI3K in the IIS pathway [17]. Moreover, phosphorylation of PKB and tGPH reporter localisation [18], both readouts of IIS pathway activity, were impaired in lnk mutants [17]. Lnk is the unique Drosophila member of the SH2B protein family. This protein family is characterised by several conserved domains: the N-terminal proline-rich stretch, a pleckstrin homology (PH) domain, a Src homology 2 (SH2) domain, and a C-terminal c-Cbl recognition motif [19-21]. Alleles with
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