A small molecule reveals role of insulin receptor-insulin like growth factor-1 receptor heterodimers

Abstract

The insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are heterodimers consisting of 2 extracellular α-subunits and 2 transmembrane β-subunits. IR α/β and IGF-1R α/β hemi-receptors can heterodimerize to form hybrids composed of one IR α/β and one IGF-1R α/β. Widely distributed in mammalian tissues, in contrast to IR and IGF-1R 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 (HUVECs) with no effect on IR or IGF-1R. Downstream of IR and IGF-1R our small molecule led to reduced expression of the negative regulatory p85α 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 EC physiology distinct from IR and IGF1R.