Vascular endothelial growth factor receptors: Molecular mechanisms of activation and therapeutic potentials

Abstract

Angiogenesis-associated eye diseases are among the most common cause of blindness in the United States and worldwide. Recent advances in the development of angiogenesis-based therapies for treatment of angiogenesis-associated diseases have provided new hope in a wide variety of human diseases ranging from eye diseases to cancer. One group of growth factor receptors critically implicated in angiogenesis is vascular endothelial growth factor receptors (VEGFR), a subfamily of receptor tyrosine kinases (RTKs). VEGFR-1 and VEGFR-2 are closely related receptor tyrosine kinases and have both common and specific ligands. VEGFR-1 is a kinase-impaired RTK and its kinase activity is suppressed by a single amino acid substitution in its kinase domain and by its carboxyl terminus. VEGFR-2 is highly active kinase, stimulates a variety of signaling pathways and broad biological responses in endothelial cells. The mechanisms that govern VEGFR-2 activation, its ability to recruit signaling proteins and to undergo downregulation are highly regulated by phosphorylation activation loop tyrosines and its carboxyl terminus. Despite their differential potentials to undergo tyrosine phosphorylation and kinase activation, both VEGFR-1 and VEGFR-2 are required for normal embryonic development and pathological angiogenesis. VEGFR-1 regulates angiogenesis by mechanisms that involve ligand trapping, receptor homodimerization and heterodimerization. This review highlights recent insights into the mechanism of activation of VEGFR-1 and VEGFR-2, and focuses on the signaling pathways employed by VEGFR-1 and VEGFR-2 that regulate angiogenesis and their therapeutic potentials in angiogenesis-associated diseases.

Endothelial monocyte activating polypeptide II interferes with VEGF-induced proangiogenic signaling

“…Between VEGFR1 and VEGFR2, the extracellular domain homology is 33.3% and cytoplasmic region homology is 54.6%, whereas kinase domain is the most conserved region with 70.1% homology. 33 We do not know where exactly EMAP II binds to the VEGFRs, but suspect that this binding is the cardinal event in the mediated inhibition of VEGFrelated signaling events. In addition, whereas our ELISA data support specific binding between EMAP II and VEGFR, steric hindrance cannot be entirely excluded to partake in this inhibitory effect.…”

Vascular endothelial growth factor in eye disease

“…Guided by the binding properties of the ligands, VEGFRs form both homodimers and heterodimers (Rahimi, 2006). The signal transduction properties of the VEGFR heterodimers, compared with homodimers, remain to be fully elucidated.…”

“…Agents that Inhibit VEGF Receptors-VEGFR-2 has a lower affinity for VEGF than does VEGFR-1, but the receptor tyrosine kinase activity of VEGFR-2 is considered more involved in angiogenic processes (Rahimi, 2006). VEGFR-1 may be involved in angiogenic processes as well when it heterodimerizes with VEGFR-2, but it is also believed to sequester VEGF, preventing it from interacting with VEGFR-2 (Hiratsuka et al, 1998).…”

Identification of PDCL3 as a Novel Chaperone Protein Involved in the Generation of Functional VEGF Receptor 2

“…VEGFR-2 2 is a receptor tyrosine kinase whose activity is paramount for vascular development during embryogenesis and pathological angiogenesis in diseases such as cancer and wet age-related macular degeneration (5,6). Upon binding to the VEGF family of ligands, VEGFR-2 forms a dimer, resulting in its increased tyrosine kinase activity and phosphorylation of multiple cytoplasmic tyrosine residues by serving docking sites for downstream effectors of VEGFR-2 (3,6,7). Given the critical role of VEGFR-2 signaling in diverse pathological conditions (1,8), regulation of VEGFR-2 expression and function represent important rate-limiting mechanisms for angiogenesis.…”