Loss of PTPRB function remodels VEGFR1 activation in tumors overexpressing the receptor tyrosine kinase

Abstract

The VEGF Receptor-1 (VEGFR1) is a deceptive receptor tyrosine kinase (RTK). In early embryonic development, VEGFR1 negatively regulates angiogenesis by acting like a decoy receptor. Ligand binding transiently phosphorylates the receptor and induces a weak activation, even at high receptor density. Yet, in multiple cancers, overexpression of VEGFR1 plays a central role in tumor vascularization and growth. Unlike many pro-oncogenic RTKs, extensive patient data analysis revealed no somatic mutation in VEGFR1 that may spontaneously activate the tyrosine kinase. The mechanism by which VEGFR1 is activated in cancers has remained an open question for more than two decades. Here, we evaluated the multi-omics profiles of VEGFR1 and its regulators in a pan-cancer database. We observed an inverse correlation between VEGFR1 and PTPRB phosphatase expression in KIRC patients and disease outcome. We observed that patients overexpressing VEGFR1 and deficient in PTPRB expression have a lower likelihood of survival. Using super-resolution single-cell imaging, we discovered that inhibiting PTPRB spontaneously activates VEGFR1 by inducing ligand-independent dimerization, possibly by shifting the equilibrium toward the active state. PTPRB inhibition induces sustained, ligand-dependent phosphorylation of VEGFR1, which may promote tumor vascularization. We conclude that a subtle phosphatase imbalance is fundamental in determining VEGFR1s role in pathological angiogenesis in tumors.