VEGFR and type-V RTK activation and signaling

Abstract

Vascular endothelial growth factor receptors (VEGFRs) in vertebrates play essential roles in the regulation of angiogenesis and lymphangiogenesis. VEGFRs belong to the receptor-type tyrosine kinase (RTK) supergene family. They consist of a ligand-binding region with seven immunoglobulin (7 Ig) -like domains, a trans-membrane (TM) domain, and a tyrosine kinase (TK) domain with a long kinase insert (KI) (also known as a type-V RTK). Structurally, VEGFRs are distantly related to the members of the M-colony stimulating factor receptor/platelet-derived growth factor receptor (CSFR)/(PDGFR) family, which have five immunoglobulin (5 Ig)-like domains. However, signal transduction in VEGFRs significantly differs from that in M-CSFR/PDGFRs. VEGFR2, the major signal transducer for angiogenesis, preferentially uses the phospholipase Cγ-protein kinase C (PLC-γ-PKC)-MAPK pathway, whereas M-CSFR/PDGFRs use the PI3 kinase-Ras-MAPK pathway for cell proliferation. In phylogenetic development, the VEGFR-like receptor in nonvertebrates appears to be the ancestor of the 7 Ig- and 5 Ig-RTK families because most nonvertebrates have only a single 7 Ig-RTK gene. In mammals, VEGFRs are deeply involved in pathological angiogenesis, including cancer and inflammation. Thus, an efficient inhibitor targeting VEGFRs could be useful in suppressing various diseases.

Figure 1.

The VEGF-VEGFR system and its inhibitors. VEGF (VEGF-A) and its receptors, VEGFR1 and VEGFR2, play a major role in vasculogenesis and angiogenesis. VEGFR3 regulates not only lymphangiogenesis but also angiogenesis under pathological conditions. Neuropilins (Nrp)-1 and Nrp-2 function as coreceptors for VEGFR1 and VEGFR2, respectively, and efficiently stimulate VEGFR signaling. A heterodimer formed between two receptors, such as VEGFR1/VEGFR2 and VEGFR2/VEGFR3, was reported to regulate angiogenesis as well as lymphangiogenesis. Various inhibitors were developed to suppress this system, and some of them are now widely used clinically.

Figure 2.

VEGFR1 has dual roles, positive and negative, in angiogenesis. VEGFR1 has a strong binding affinity for VEGF, but its kinase activity is much weaker than that of VEGFR2. VEGFR1 knockout mice (i.e., flt-1^−/− mice) die during early embryogenesis because of overgrowth of angiogenesis, indicating a negative role for VEGFR1 in angiogenesis. VEGFR1-signal-deficient mice (i.e., flt-1 TK^−/− mice), organize blood vessel structure in a normal manner. Thus, the negative function of VEGFR1 localizes to the ligand-binding domain. flt-1 TM-TK^−/− mice indicate that about half of littermates are healthy but the other half are embryonic lethal due to poor development of blood vessels.

Figure 3.

sFlt-1: An endogenous VEGF-inhibitor intimately related to preeclampsia. The soluble form of VEGFR1, sFlt-1, is expressed in normal placenta, particularly in the trophoblasts. Expression of the sFlt-1 gene is abnormally increased in preeclampsia patients, and the excess sFlt-1 is distributed via the bloodstream to various maternal tissues. sFlt-1 traps endogenous VEGF, resulting in hypertension and proteinuria.

Figure 4.

A unique signaling pathway from VEGFR2 toward angiogenesis. The Y1175 site is one of the major autophosphorylation sites on VEGFR2 after stimulation with VEGF. The pY1175-containing motif is the binding and activation site for PLC-γ. It stimulates PKC-Raf-MEK-MAPK and calcium mobilization pathways for EC activation and proliferation.

Figure 5.

Phylogenetic development of the 7 Ig-RTKs (VEGFRs) and the 5 Ig-RTKs: A hypothesis. Most nonvertebrates carry a single 7 Ig-RTK gene. Double cis gene duplication followed by double trans gene duplication appears to have generated the 7 Ig-RTK and 5 Ig-RTK supergene families in vertebrates.