A small molecule reveals role of insulin receptor-insulin like growth factor-1 receptor heterodimers
The insulin receptor and insulin like growth factor-1 receptor are heterodimers consisting of two extracellular -subunits and two transmembrane {beta}-subunits. IR {beta} and IGF1R {beta} hemi-receptors can heterodimerize to form hybrids composed of one IR {beta} and one IGF1R {beta}. Widely distributed in mammalian tissues, in contrast to IR and IGF1R the physiological function of hybrids is unclear. To identify tool compounds that inhibit hybrid formation we performed a high-throughput small molecule screen based on a homology model of hybrid structure. Our studies unveil a first in class quinoline-containing heterocyclic small molecule that reduces hybrids by >50% in human umbilical vein endothelial cells with no effect on IR or IGF1R expression. Downstream of IR and IGF1R our small molecule led to reduced expression of the negative regulatory p85 subunit of phosphatidylinositol 3-kinase, an increase in phosphorylation of its downstream target Akt and enhanced insulin and shear-induced phosphorylation of Akt. We show that hybrids have a role in human endothelial cell physiology distinct from IR and IGF1R.