A type 2 diabetes disease module with a high collective influence for Cdk2 and PTPLAD1 is localized in endosomes

Abstract

1Despite the identification of many susceptibility genes our knowledge of the underlying mechanisms 2 responsible for complex disease remains limited. Here, we identified a type 2 diabetes disease 3 module in endosomes, and validate it for functional relevance on selected nodes. Using hepatic 4Golgi/endosomes fractions, we established a proteome of insulin receptor-containing endosomes 5 that allowed the study of physical protein interaction networks on a type 2 diabetes background. 6The resulting collated network is formed by 313 nodes and 1147 edges with a topology organized 7 around a few major hubs with Cdk2 displaying the highest collective influence. Overall, 88% of the 8 nodes are associated with the type 2 diabetes genetic risk, including 101 new candidates. The Type 9 2 diabetes module is enriched with cytoskeleton and luminal acidification -dependent processes that 10 are shared with secretion-related mechanisms. We identified new signaling pathways driven by 11Cdk2 and PTPLAD1 whose expression regulate the association of the insulin receptor with TUBA, 12 TUBB, the actin component ACTB and the endosomal sorting markers Rab5c and Rab11a. 13