Tyrosine Kinase Receptor Flt/VEGFR Family: Its Characterization Related to Angiogenesis and Cancer

Abstract

Ligands and their tyrosine kinase (TK) receptors regulate a variety of biological systems in animals. Vascular endothelial growth factor (VEGF) and its receptor (Flt/VEGFR family) system play a crucial role not only in physiological but also in most parts of pathological angiogenesis including cancer. Flt-1/VEGFR-1 and KDR/VEGFR-2 bind VEGF-A but have different functions on angiogenesis at early embryogenesis: Flt-1 has a negative role by trapping ligands, whereas KDR (Flk1 in mice) exerts a strong positive signal, resulting in a balance in blood vessel formation. At adult stages, however, both VEGFRs contribute to pathological angiogenesis either directly or through stimulation of migration/activation of macrophage lineage cells and stimulate tumor growth, metastasis, and inflammation. VEGFRs activate downstream signaling of the phospholipase Cγ-protein kinase C-MAP kinase pathway but not Ras pathway for cell proliferation. The VEGF-C/D and Flt-4/VEGFR-3 system regulates lymphangiogenesis. Thus, VEGFs as well as these receptor TKs are attractive targets for suppressing pathological angiogenesis.

Domain I-IV of β2-glycoprotein I inhibits advanced glycation end product-induced angiogenesis by down-regulating vascular endothelial growth factor 2 signaling

“…VEGF, particularly VEGF-A, is a key factor promoting angiogenesis by binding with its receptors, VEGFR-1 and VEGFR-2. VEGFR-2 has a more dominant role in angiogenesis, while VEGFR-1 is involved mainly in the migration of macrophages and vascular endothelial cells (15). VEGF activates VEGFR and the downstream phosphoinositide 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/ERK1/2 signaling pathways (16,17) and promotes angiogenesis.…”

“…AGE is important in diabetic retinopathy, particularly in PDR (14,15). It is reported that AGE promotes neovascularization by increasing the expression of VEGF (mainly VEGF-A) in endothelial cells and consequently inducing tube formation of the retinal microvessel endothelial cells (23).…”

Association between kinase insert domain-containing receptor gene polymorphisms and silent brain infarction: A Korean study

“…However, no clear explanation is available due to conflicting results regarding the influence of VEGF-KDR signaling on blood vessels as well as the complex roles of VEGF-KDR signaling [24][25][26][27][28][29][30][31][32]. VEGF-KDR system plays a critical role not only physiological but also in most parts of pathological angiogenesis.…”

Aflibercept a new target therapy in cancer treatment: a review

“…The biological effects of VEGF-A include endothelial cell proliferation, survival, migration, invasion, chemotaxis of bone marrow progenitors, vascular permeability, and vasodilation, which are mediated by its binding and activation of receptor tyrosine kinases VEGFR-1 and VEGFR-2 (Ellis and Hicklin, 2008). Although VEGF-A binds VEGFR-1 with approximately 10 times higher affinity than VEGFR-2, the higher kinase activity of VEGFR-2 makes it the most important effector of VEGF-A signaling (Shibuya, 2010;Shalaby et al, 1995). VEGF-A is the best-characterized member of the VEGF family.…”

“…Aflibercept is a soluble recombinant fusion protein designed to block the angiogenesis network binding to all isoforms of VEGF and to placental growth factor (Kim et al, 2002a;Holash et al, 2002). It developed by fusing sections of second immunoglobulin (Ig) domain of VEGFR-1 and the third Ig domain of VEGFR-2 to the Fc portion of human IgG (Shibuya, 2010;Inai et al, 2004;Huang et al, 2003).…”