Abstract
The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) play crucial roles in vasculogenesis and angiogenesis. Angiogenesis is an important mechanism in many physiological and pathological processes, and is involved in endothelial cell proliferation, migration, and survival, then leads to further tubulogenesis, and finally promotes formation of vessels. This series of signaling cascade pathways are precisely mediated by VEGF/VEGFR-2 system. The VEGF binding to the IgD2 and IgD3 of VEGFR-2 induces the dimerization of the receptor, subsequently the activation and trans-autophosphorylation of the tyrosine kinase, and then the initiation of the intracellular signaling cascades. Finally the VEGF-activated VEGFR-2 stimulates and mediates variety of signaling transduction, biological responses, and pathological processes in angiogenesis. Several crucial phosphorylated sites Tyr801, Try951, Try1175, and Try1214 in the VEGFR-2 intracellular domains mediate several key signaling processes including PLCγ-PKC, TSAd-Src-PI3K-Akt, SHB-FAK-paxillin, SHB-PI3K-Akt, and NCK-p38-MAPKAPK2/3 pathways. Based on the molecular structure and signaling pathways of VEGFR-2, the strategy of the VEGFR-2-targeted therapy should be considered to employ in the treatment of the VEGF/VEGFR-2-associated diseases by blocking the VEGF/VEGFR-2 signaling pathway, inhibiting VEGF and VEGFR-2 gene expression, blocking the binding of VEGF and VEGFR-2, and preventing the proliferation, migration, and survival of vascular endothelial cells expressing VEGFR-2.
Highlights
In vascular endothelial growth factors (VEGFs)/VEGFs and their receptors (VEGFRs)-2 system, the VEGF binding to the Ig-like subdomains 2 and 3 (IgD2 and IgD3) of VEGFR-2 induces the dimerization of the receptor, the activation and trans-autophosphorylation of the tyrosine kinase, and the initiation of the intracellular signaling cascades, is involved in proliferation, survival, migration, and permeability of vascular endothelial cells
The interaction of VEGF and VEGFR-2 is crucial for the dimerization of VEGFR-2
The signaling by VEGFR-2 requires VEGF-mediated dimerization with precise positioning of VEGFR-2 subunits in active dimers
Summary
Various physiological and pathological processes are involved in vasculogenesis, angiogenesis, and formation and maintenance of new blood vessel structures, including embryonic development (Vallon et al, 2014), tissue growth and wound healing (Ivkovic et al, 2003), tumorigenesis (Yehya et al, 2018), rheumatoid arthritis (Marrelli et al, 2011), diabetic retinopathy (Crawford et al, 2009; Cheng and Ma, 2015), axon growth (Klagsbrun and Eichmann, 2005), cancer (Hanahan and Folkman, 1996; Rajabi and Mousa, 2017; Li et al, 2020), and inflammation (Alkim et al, 2015), which are stimulated by a variety of factors, including basic fibroblast growth factor (bFGF) (Iwasaki et al, 2004), vascular endothelial growth factor (VEGF) Vascular endothelial growth factors are main regulators in vasculogenesis and angiogenesis and play their roles by binding to VEGFRs on cell surface and activating subsequently the signaling pathways of angiogenesis. VEGFR-2 is composed of a signal peptide, a extracellular domain (ECD) including seven Ig-like subdomains (IgD1∼7), a TMD, a JMD, a catalytic tyrosine kinas domain (TKD) including ATP binding domain (TKD1), kinase insert domain (KID) and phosphotransferase domain (TKD2), and a flexible C-terminal domain (CTD), and many functional sites. Similar to other receptor tyrosine kinases (RTKs), cellular signaling mediated by VEGFR-2 is stimulated and initiated upon binding of its ligand dimer to the extracellular receptor Ig-like domains 2 and 3 (Ruch et al, 2007) This ligand-receptor interaction causes VEGFR-2 homo- and hetero-dimerization followed by phosphorylation of specific tyrosine residues located in the intracellular region including juxtamembrane domain, tyrosine kinas domain, and the carboxy-terminal domain. A variety of signaling molecules are recruited to VEGFR-2 dimers that activate downstream signaling pathways, and affect the physiological characteristics of endothelial cells and the entire vascular environment (Figure 2A; Fuh et al, 1998; Ruch et al, 2007; Ma et al, 2011)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
