Discovery of High-Affinity PDGF-VEGFR Interactions: Redefining RTK Dynamics.

ABSTRACT: Nearly all studies of angiogenesis have focused on uni-family ligand-receptor binding, e.g., VEGFs bind to VEGF receptors, PDGFs bind to PDGF receptors, etc. The discovery of VEGF-PDGFRs binding challenges this paradigm and calls for investigation of other ligand-receptor binding possibilities. We utilized surface plasmon resonance to identify and measure PDGF-to-VEGFR binding rates, establishing cut-offs for binding and non-binding interactions. We quantified the kinetics of the recent VEGF-A:PDGFR? interaction for the first time with K_D?=?340 pM. We discovered new PDGF:VEGFR2 interactions with PDGF-AA:R2 K_D?=?530?nM, PDGF-AB:R2 K_D?=?110 pM, PDGF-BB:R2 K_D?=?40?nM, and PDGF-CC:R2 K_D?=?70 pM. We computationally predict that cross-family PDGF binding could contribute up to 96% of VEGFR2 ligation in healthy conditions and in cancer. Together the identification, quantification, and simulation of these novel cross-family interactions posits new mechanisms for understanding anti-angiogenic drug resistance and presents an expanded role of growth factor signaling with significance in health and disease.

SUBMITTER: Mamer SB 

PROVIDER: S-EPMC5704011 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature