Insulin receptor-MAD2 complex in obesity-related cancer

Alterations of insulin signaling have been linked to diabetes. Insulin is a potent mitogen, and hyperinsulinemia can promote tumor growth. Thus, understanding insulin action in tumor progression is of paramount importance. The spindle checkpoint ensures the fidelity of chromosome segregation. The key checkpoint protein MAD2 forms a mitotic checkpoint complex (MCC) that arrests cells in mitosis. We discovered a non-canonical role of spindle checkpoint proteins in insulin signaling. MAD2 binds to the insulin receptor (IR), recruits the clathrin adaptor complex by assembling an MCC-like complex, and promotes IR endocytosis. Mice in which MAD2 binding to IR is prevented by point mutations (IR4A) display increased T-cell aneuploidy and T-cell lymphoma. These results have opened up new areas of research on how nutrient signaling affects chromosome stability. We will pursue this observation with 2 aims: in Aim 1 we will determine the function and mechanism of IR in chromosome stability by testing whether IR4A/4A mice develop aneuploidy in vivo using single-cell sequencing and karyotyping.

In Aim 2, we will establish the role of the IR-MAD2 interaction in metabolism. These experiments will advance our understanding of the function, regulation, and mechanism(s) of insulin action in cell proliferation.