The goal of our research is to delineate mechanisms underlying the mutual regulation between cell division and metabolism by combining mouse genetics, cell biology, biochemistry and cryo-EM structure. Perturbation of this regulation leads to cancer and metabolic diseases. We have discovered a critical role of cell division regulators in insulin signaling through regulating insulin receptor endocytosis. Our findings link aneuploidy-suppressing genes to insulin signaling and suggest a mechanism by which a circulating hormone may regulate genomic stability. Our laboratory will study the role of cell division regulators in insulin signaling, and we will expand it to other receptor tyrosine kinases to discover how systemic signaling communicates with cell division process to maintain both genomic stability and metabolic homeostasis.
Recently, we discovered that large-scale conformational change of insulin receptor driven by insulin binding relieves its auto-inhibition, triggering trans-autophosphorylation of the kinase domain and hence initiation of downstream signaling cascade. How this conformational change induces kinase activation, how the activated kinase selectively provokes the signaling branch, and how the active insulin receptor can be preferentially internalized are not fully understood. Our laboratory will reveal how insulin activates the receptor kinase and insulin signaling, and initiates the receptor endocytosis at the molecular level, and how this process maintains systemic homeostasis in vivo. Along the way, we hope to unravel new molecular targets that will be useful to treat two very prevalent diseases, Diabetes and Cancer.