Annexin A2 is SUMOylated on its N-terminal domain: Regulation by insulin

•Annexin A2 is SUMOylable in its N-terminal domain.•AnnexinA2 SUMOylation is regulated by insulin.•A protein–protein interactions network (IRASGEN) connects annexinA2 SUMOylation to actin and microtubule-mediated trafficking.•41% of IRASGEN have common heritable variants associated with type 2 diabetes.

Insulin receptor (IR) endocytosis requires a remodelling of the actin cytoskeleton. We show here that ANXA2 is SUMOylated at the K10 located in a non-consensus SUMOylation motif in the N-terminal domain. The Y24F mutation decreased the SUMOylation signal, whereas insulin stimulation increased ANXA2 SUMOylation. A survey of protein SUMOylation in hepatic Golgi/endosome (G/E) fractions after insulin injections revealed the presence of a SUMOylation pattern and confirmed the SUMOylation of ANXA2. The construction of an IR/ANXA2/SUMO network (IRASGEN) in the G/E context reveals the presence of interacting nodes whereby SUMO1 connects ANXA2 to actin and microtubule-mediated changes in membrane topology. Heritable variants associated with type 2 diabetes represent 41% of the IRASGEN thus pointing out the physio-pathological importance of this subnetwork.