What is it about?
Despite the identification of many susceptibility genes our knowledge of the mechanisms underlying complex disease remains limited. Here, we identified a type 2 diabetes disease module in endosomes, and validate it for functional relevance on selected nodes including CDK2 and PTPLAD1
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Why is it important?
Using hepatic Golgi/endosomes fractions, we established a proteome of insulin receptor-containing endosomes that allowed the study of physical protein interaction networks on a type 2 diabetes background. The resulting collated network is formed by 313 nodes and 1147 edges with a topology organized around a few major hubs with Cdk2 displaying the highest collective influence. In addition to genes associated to type-2 diabetes risk, we propose 101 new candidates. The Type 2 diabetes module is enriched with cytoskeleton and luminal acidification–dependent processes that are shared with secretion-related mechanisms. We identified new signaling pathways driven by Cdk2 and PTPLAD1 whose expression affects the association of the insulin receptor with TUBA, TUBB, the actin component ACTB and the endosomal sorting markers Rab5c and Rab11a. Therefore, the interactome of internalized insulin receptors reveals the presence of a type 2 diabetes disease module enriched in new layers of signaling feedback loops required for insulin signaling, clearance and islet biology.
Perspectives
Our results establish that the endosomal apparatus contains a Type-2 diabetes disease module located in close proximity to the IR. It senses the state of insulin receptor activation and seems co-functional with insulin secretion and islets biology. It helps to explain disease heterogeneity and represents a valuable new resource to understand insulin action and to classify related metabolic traits . Rewiring a network, distorted under the combined genetic and environmental pressures, with designed surface interactors, provides a mechanistic rationale for the exploration of personalized medicine and elaborate new necessary drugs.
Martial Boutchueng Djidjou
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This page is a summary of: A type 2 diabetes disease module with a high collective influence for Cdk2 and PTPLAD1 is localized in endosomes, PLOS One, October 2018, PLOS,
DOI: 10.1371/journal.pone.0205180.
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