Molecular basis of VEGFR1 autoinhibition at the plasma membrane

Author:

Chakraborty Manas Pratim,Das Diptatanu,Mondal Purav,Kaul PragyaORCID,Bhattacharyya Soumi,Das Prosad Kumar,Das Rahul

Abstract

AbstractLigand-independent activation of VEGFR is a hallmark in diabetes and several cancers. Like most RTKs, the VEGFR2, the primary VEGF receptor, is activated spontaneously at higher receptor concentrations. An exception is VEGFR1, which remains constitutively inactive in the basal state. Ligand stimulation transiently phosphorylates VEGFR1 and induces weak kinase activation in endothelial cells. Recent studies, however, suggest that VEGFR1 signaling is indispensable in regulating various physiological or pathological events, which is puzzling. Why VEGFR1 is differentially regulated is an open question. Here we elucidate a mechanism of juxtamembrane inhibition that shifts the equilibrium more to the inactive state, rendering VEGFR1 an inefficient kinase. Our data suggest that a combination of tyrosine phosphatase activity and JM inhibition suppress the basal phosphorylation of VEGFR1. We conclude that a subtle imbalance in phosphatase activation or removing juxtamembrane inhibition is sufficient to induce basal activation of VEGFR1 and remodel tyrosine phosphorylation to be sustained.

Publisher

Cold Spring Harbor Laboratory

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