Tying the knot: The cystine signature and molecular-recognition processes of the vascular endothelial growth factor family of angiogenic cytokines

Abstract

The cystine-knot motif, made up of three intertwined disulfide bridges, is a unique feature of several toxins, cyclotides and growth factors, and occurs in a variety of species, including fungi, insects, molluscs and mammals. Growth factor molecules containing the cystine-knot motif serve as ligands for a diverse range of receptors and play an important role in extracellular signalling. This superfamily of polypeptides comprises several homodimeric and heterodimeric molecules that are central characters in both health and disease. Amongst these molecules are a group of proteins that belong to the vascular endothelial growth factor (VEGF) subfamily. The members of this family are known angiogenic factors that regulate processes leading to blood vessel formation in physiological and pathological conditions. The focus of the present review is on the structural characteristics of proteins that belong to the VEGF family and on signal-transduction pathways that become initiated via the VEGF receptors. The family of vascular endothelial growth factors (VEGFs) includes VEGF-A, -B, -C, -D, -E, -F and placenta growth factor (PlGF). The VEGF family proteins bind to three receptor tyrosine kinases: VEGF receptor-1, -2, and -3. Neuropilins and heparan-sulfated proteoglycans act as co-receptors to these proteins. VEGF proteins stimulate unique cellular responses by mediating receptor dimerization and become activated through transphosphorylation © 2011 The Authors Journal compilation © 2011 FEBS.