RT Journal Article
SR Electronic
T1 A small molecule reveals role of insulin receptor-insulin like growth factor-1 receptor heterodimers
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.09.471780
DO 10.1101/2021.12.09.471780
A1 Katie J Simmons
A1 Chloe G Myers
A1 Hema Viswambharan
A1 Natalie J Haywood
A1 Katherine Bridge
A1 Samuel Turvey
A1 Thomas Armstrong
A1 Lydia Lunn
A1 Paul J Meakin
A1 Eva Clavane
A1 David J Beech
A1 Richard M Cubbon
A1 Stephen B Wheatcroft
A1 Martin J McPhillie
A1 Colin WG Fishwick
A1 Mark T Kearney
YR 2021
UL http://biorxiv.org/content/early/2021/12/09/2021.12.09.471780.abstract
AB The insulin receptor and insulin like growth factor-1 receptor are heterodimers consisting of two extracellular α-subunits and two transmembrane β-subunits. IR αβ and IGF1R αβ hemi-receptors can heterodimerize to form hybrids composed of one IR αβ and one IGF1R αβ. 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 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 endothelial cell physiology distinct from IR and IGF1R.Competing Interest StatementThe authors have declared no competing interest.