Partners and International Organizations
(English)
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AT, BE, CY, CZ, DK, FR, DE, EL, HU, IE, IL, IT, LT, LU, NL, NO, PT, RO, CS, SK, SI, ES, SE, CH, UK
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Abstract
(English)
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The proper regulation of blood glucose homeostasis in mammals requires an adequate relation between the capacity to produce insulin and metabolic demand. Insulin receptor substrate proteins (IRS) are signalling intermediates that are required to keep this balance because they are needed for insulin action in target tissues but also for insulin production in pancreatic beta-cells. At the molecular level IRS proteins act as adapters between ligand-activated insulin receptor and various downstream signalling components allowing the induction of cellular responses, like enhanced uptake of glucose into muscle and fat, proliferation or cell growth. It has been found that insulin sensitivity and beta-cell mass/function are both modulated in vivo by Ser/Thr phosphorylation of IRS1 and IRS2. To extend our understanding of the mechanisms of signal transduction via IRS and to define new drug targets for the treatment of type 2 diabetes we applied the yeast 2-hybrid system and identified six new binding partners of IRS1 and IRS2. All but one of these novel IRS interacting proteins have known functions. Their interaction with IRS might point to co-ordination of insulin signal transduction with cellular systems such as the cytoskeleton, the ER and mitochondria. Especially the ER is currently discussed as one of the major culprits in obesity-induced insulin resistance. The cellular response to ER stress, called unfolded protein response (UPR), activates c-Jun N-terminal kinase (JNK) and thereby represses IRS function. A component of the UPR emerged as a new binding partner of IRS1 and IRS2 from our two hybrid screens and we are currently investigating if this interaction could be the mediator of ER stress-induced insulin resistance.
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