Signal transduction by vascular endothelial growth factor receptors

Abstract

Vascular endothelial growth factors (VEGFs) are master regulators of vascular development and of blood and lymphatic vessel function during health and disease in the adult. It is therefore important to understand the mechanism of action of this family of five mammalian ligands, which act through three receptor tyrosine kinases (RTKs). In addition, coreceptors like neuropilins (NRPs) and integrins associate with the ligand/receptor signaling complex and modulate the output. Therapeutics to block several of the VEGF signaling components have been developed with the aim to halt blood vessel formation, angiogenesis, in diseases that involve tissue growth and inflammation, such as cancer. In this review, we outline the current information on VEGF signal transduction in relation to blood and lymphatic vessel biology.

Figure 1.

VEGF binding specificities and VEGFR signaling complexes. Five vascular endothelial growth factors, VEGFA, VEGFB, VEGFC, VEGFD, and PlGF, bind with different affinities to three VEGF receptor tyrosine kinases (VEGFR) and two NRP coreceptors initiating homo- and heterodimer formation. Proteolytic processing of VEGFC and VEGFD allows binding to VEGFR2. Extracellular domains of VEGFRs and NRPs involved in VEGF binding are indicated by hatched circles. PlGF, placenta growth factor; sVEGFR1, soluble VEGFR1; sVEGFR2, soluble VEGFR2; TMD, transmembrane domain; JMD, juxtamembrane domain; TKD1, ATP binding domain; KID, kinase insert domain; TKD2, phosphotransferase domain; CTD, carboxy-terminal domain.

Figure 2.

Tyrosine phosphorylation sites in VEGFRs. Intracellular domains of VEGFR monomers are shown schematically with phosphorylated tyrosine residues indicated as Y followed by a number indicating the position in the amino acid sequence of the receptor. Red numbers indicate selective phosphorylation, i.e., Y1309 in VEGFR1 is phosphorylated on PlGF-, but not VEGF-binding, Y951 in VEGFR2 is phosphorylated in endothelial cells without pericyte contact, and Y1337/Y1363 are phosphorylated in VEGFR3 homodimers, but not in VEGFR2/-3 heterodimers. Tyrosines with identified biological function are bold; tyrosines without known biological function are regular. Encircled residues in VEGFR3 show tyrosines, phosphorylated by extracellular matrix independent of ligand (see text for details and references). Functions are indicated for respective tyrosines in italic. TMD, Transmembrane domain; JMD, juxtamembrane domain; TKD1, ATP binding domain; KID, kinase insert domain; TKD2, phosphotransferase domain; CTD, carboxy-terminal domain; EC, endothelial cell.

Figure 3.

VEGFA165-mediated signal transduction of VEGFR2. The coordinated arrangement of endothelial cells in three dimensions to form and maintain a vascular tube requires endothelial cell proliferation, migration, survival, and permeability. These biological responses are mediated mainly by VEGFA-activated VEGFR2, via a complex network of intracellular signal transduction pathways. On VEGFA-binding to extracellular Ig-like domains 2 and 3 of VEGFR2, signaling molecules bind to respective phosphorylation sites (indicated by numbers) in the intracellular domain of VEGFR2 and activate downstream mediators (ovals) resulting in biological responses such as proliferation, migration, survival and permeability. ER, Endoplasmic reticulum. See text for details.

Figure 4.

Internalization of VEGFR2. In resting endothelial cells, VE-cadherin prevents internalization of VEGFR2 by physical interaction and recruitment of the DEP-1 phosphatase, which dephosphorylates VEGFR2 to maintain its inactivated state. On VEGF binding, VEGFR2 is released from VE-cadherin or Caveolin-1 followed by activation of signaling cascades and subsequent internalization. VEGFR2 continues to signal from endosomes and eventually becomes ubiquitinated and degraded. See text for details. Note that the exact stoichiometry of the different complexes is unknown. VEC, VE-cadherin.