The cellular response to vascular endothelial growth factors requires co-ordinated signal transduction, trafficking and proteolysis

Abstract

SynopsisVEGFs (vascular endothelial growth factors) are a family of conserved disulfide-linked soluble secretory glycoproteins found in higher eukaryotes. VEGFs mediate a wide range of responses in different tissues including metabolic homoeostasis, cell proliferation, migration and tubulogenesis. Such responses are initiated by VEGF binding to soluble and membrane-bound VEGFRs (VEGF receptor tyrosine kinases) and co-receptors. VEGF and receptor splice isoform diversity further enhances complexity of membrane protein assembly and function in signal transduction pathways that control multiple cellular responses. Different signal transduction pathways are simultaneously activated by VEGFR-VEGF complexes with membrane trafficking along the endosome-lysosome network further modulating signal output from multiple enzymatic events associated with such pathways. Balancing VEGFR-VEGF signal transduction with trafficking and proteolysis is essential in controlling the intensity and duration of different intracellular signalling events. Dysfunction in VEGF-regulated signal transduction is important in chronic disease states including cancer, atherosclerosis and blindness. This family of growth factors and receptors is an important model system for understanding human disease pathology and developing new therapeutics for treating such ailments.

Expression of VEGFR-2 during Liver Regeneration after Partial Hepatectomy in a Bioluminescence Mouse Model

“…The effects of VEGF are mediated through cell surface receptor tyrosine kinases VEGFR-1, VEGFR-2, and VEGFR-3. The majority of VEGF-regulated proangiogenic effects are attributed to interaction with VEGFR-2 [4]. VEGFR-2 is encoded by the flk1 gene (mouse fetal liver kinase 1), also known as KDR (kinase insert domain receptor) in humans [5].…”

Tetrandrine suppresses lung cancer growth and induces apoptosis, potentially via the VEGF/HIF-1α/ICAM-1 signaling pathway

“…VEGF is highly expressed in ovarian cancer, breast carcinoma, gastric carcinoma and urinary bladder carcinoma (17). VEGF expression levels are positively associated with advanced tumor grade, malignancy and vasculogenesis in tumor tissues (18).…”

Modulating carbohydrate–protein interactions through glycoengineering of monoclonal antibodies to impact cancer physiology

“…Third, the Fab can interfere with angiogenesis by blocking interactions between glycans and VEGF, a key inducer for several downstream signaling pathways (e.g., MAPK and PI3K/AKT [17]) that lead to vascular and stromal cell ablation [18]. Bevacizumab binds VEGF to interrupt interactions between VEGF and heparin sulfate proteoglycans (HSPGs), leading to VEGF-VEGFR interaction blockade [19]. Fourth, mAbs can modulate Gal1-N-linked glycan interactions.…”