Interaction of IRS2 with PLK1 protects cells from mitotic stress

In this study we identify a role for IRS2 in the protection of cells from mitotic stress through its interaction with PLK1. IRS2 is an adapter protein for the insulin and IGF-1 receptors that mediates their signaling functions. In this capacity, IRS2 is tyrosine phosphorylated to recruit signaling effectors that control cellular outcomes. A role for IRS2 in mitotic regulation has been reported, but the mechanism of IRS2 action in this regulation has not been determined. Here we report that IRS2 interacts with PLK1 in a CDK1-dependent manner. In response to mitotic stress, cells that lack IRS2 or express a PLK1-binding deficient mutant exhibit reduced centrosome separation and a shortened mitotic arrest that leads to reduced tumor cell viability. In contrast, cells expressing an IRS2 mutant that is not tyrosine phosphorylated display normal mitotic function. Together, our findings establish a mechanistic connection between IRS2 and mitotic regulation that is distinct from its function as a signaling adapter protein.