Abstract
Despite the identification of many susceptibility genes our knowledge of the underlying mechanisms responsible for complex disease remains limited. Here, we identified a type 2 diabetes disease module in endosomes, and validate it for functional relevance on selected nodes. 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. Overall, 88% of the nodes are associated with the type 2 diabetes genetic risk, including 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 feedback loops required for insulin signaling, clearance and islet biology.
Highlights
The insulin receptor (IR) belongs to the receptor tyrosine-kinase (RTK) family of cell-surface receptors [1, 2]
We started with a mixed Golgi/endosomes fraction (G/E) using a single dose of insulin (1.5 μg/100 g body weight [b.w.]) that resulted in 50% saturation of rat liver receptors
Other Rabs identified at both times (Rab6a, Rab5c, Rab1a, Rab2b, Rab11b, Rab14, Rab1b, Rab7a and Rap1b) are all implicated in recycling, transcytotic or Golgi transport events [17, 38]
Summary
The insulin receptor (IR) belongs to the receptor tyrosine-kinase (RTK) family of cell-surface receptors [1, 2]. Work on insulin and epidermal growth factor (EGF) revealed the presence of signaling molecules in hepatic endosomes fractions [3]. The concept of endosomal signaling is well established [4], but the rules underlying IR trafficking and signaling compared with. The type 2 diabetes disease module collection and analysis, decision to publish, or preparation of the manuscript
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