VEGF receptor | |
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Identifiers | |
Symbol | VEGF |
InterPro | IPR009135 |
Membranome | 1335 |
Identifiers | |||||||
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Symbol | FLT1 | ||||||
Alt. symbols | FLT | ||||||
NCBI gene | 2321 | ||||||
HGNC | 3763 | ||||||
OMIM | 165070 | ||||||
RefSeq | NM_002019 | ||||||
UniProt | P17948 | ||||||
Other data | |||||||
EC number | 2.7.1.112 | ||||||
Locus | Chr. 13 q12 | ||||||
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kinase insert domain receptor (a type III receptor tyrosine kinase) | |||||||
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Identifiers | |||||||
Symbol | KDR | ||||||
Alt. symbols | FLK1, VEGFR, VEGFR2, CD309 | ||||||
NCBI gene | 3791 | ||||||
HGNC | 6307 | ||||||
OMIM | 191306 | ||||||
RefSeq | NM_002253 | ||||||
UniProt | P35968 | ||||||
Other data | |||||||
EC number | 2.7.1.112 | ||||||
Locus | Chr. 4 q11-q12 | ||||||
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fms-related tyrosine kinase 4 | |||||||
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Identifiers | |||||||
Symbol | FLT4 | ||||||
Alt. symbols | VEGFR3, PCL | ||||||
NCBI gene | 2324 | ||||||
HGNC | 3767 | ||||||
OMIM | 136352 | ||||||
RefSeq | NM_002020 | ||||||
UniProt | P35916 | ||||||
Other data | |||||||
EC number | 2.7.1.112 | ||||||
Locus | Chr. 5 q34-q35 | ||||||
|
VEGF receptors (VEGFRs) are receptors for vascular endothelial growth factor (VEGF). [1] [2] There are three main subtypes of VEGFR, numbered 1, 2 and 3. Depending on alternative splicing, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR). [3]
Inhibitors of VEGFR are used in the treatment of cancer.
Vascular endothelial growth factor (VEGF) is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). As its name implies, VEGF activity is restricted mainly to cells of the vascular endothelium, although it does have effects on a limited number of other cell types (e.g. stimulation monocyte/macrophage migration). In vitro, VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF also enhances microvascular permeability and is sometimes referred to as vascular permeability factor.
All members of the VEGF family stimulate cellular responses by binding to tyrosine kinase receptors (the VEGFRs) on the cell surface, causing them to dimerize and become activated through transphosphorylation. The VEGF receptors have an extracellular portion consisting of 7 immunoglobulin-like domains, a single transmembrane spanning region and an intracellular portion containing a split tyrosine-kinase domain.
VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF. [1] The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling. Another function of VEGFR-1 is to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding (this appears to be particularly important during vasculogenesis in the embryo). In fact, an alternatively spliced form of VEGFR-1 (sFlt1) is not a membrane bound protein but is secreted and functions primarily as a decoy. [6] A third receptor has been discovered (VEGFR-3), however, VEGF-A is not a ligand for this receptor. VEGFR-3 mediates lymphangiogenesis in response to VEGF-C and VEGF-D.
In addition to binding to VEGFRs, VEGF binds to receptor complexes consisting of both neuropilins and VEGFRs. This receptor complex has increased VEGF signalling activity in endothelial cells (blood vessels). [7] [8] Neuropilins (NRP) are pleiotropic receptors and therefore other molecules may interfere with the signalling of the NRP/VEGFR receptor complexes. For example, Class 3 semaphorins compete with VEGF165 for NRP binding and could therefore regulate VEGF-mediated angiogenesis. [9]
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood vessel tissue, mitogenesis, i.e. proliferation, of mesenchymal cells such as fibroblasts, osteoblasts, tenocytes, vascular smooth muscle cells and mesenchymal stem cells as well as chemotaxis, the directed migration, of mesenchymal cells. Platelet-derived growth factor is a dimeric glycoprotein that can be composed of two A subunits (PDGF-AA), two B subunits (PDGF-BB), or one of each (PDGF-AB).
Vascular endothelial growth factor, originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.
An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet.
Endothelial stem cells (ESCs) are one of three types of stem cells found in bone marrow. They are multipotent, which describes the ability to give rise to many cell types, whereas a pluripotent stem cell can give rise to all types. ESCs have the characteristic properties of a stem cell: self-renewal and differentiation. These parent stem cells, ESCs, give rise to progenitor cells, which are intermediate stem cells that lose potency. Progenitor stem cells are committed to differentiating along a particular cell developmental pathway. ESCs will eventually produce endothelial cells (ECs), which create the thin-walled endothelium that lines the inner surface of blood vessels and lymphatic vessels. The blood vessels include arteries and veins. Endothelial cells can be found throughout the whole vascular system and they also play a vital role in the movement of white blood cells
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. The receptors are generally activated by dimerization and substrate presentation. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.
Angiopoietin is part of a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Angiopoietin signaling most directly corresponds with angiogenesis, the process by which new arteries and veins form from preexisting blood vessels. Angiogenesis proceeds through sprouting, endothelial cell migration, proliferation, and vessel destabilization and stabilization. They are responsible for assembling and disassembling the endothelial lining of blood vessels. Angiopoietin cytokines are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling smooth muscle cells surrounding vessels. There are now four identified angiopoietins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4.
Neuropilin is a protein receptor active in neurons.
Vascular endothelial growth factor receptor 1 is a protein that in humans is encoded by the FLT1 gene.
Kinase insert domain receptor also known as vascular endothelial growth factor receptor 2 (VEGFR-2) is a VEGF receptor. KDR is the human gene encoding it. KDR has also been designated as CD309. KDR is also known as Flk1.
Neuropilin 2 (NRP2) is a protein that in humans is encoded by the NRP2 gene.
Vascular endothelial growth factor C (VEGF-C) is a protein that is a member of the platelet-derived growth factor / vascular endothelial growth factor (PDGF/VEGF) family. It is encoded in humans by the VEGFC gene, which is located on chromosome 4q34.
Neuropilin-1 is a protein that in humans is encoded by the NRP1 gene. In humans, the neuropilin 1 gene is located at 10p11.22. This is one of two human neuropilins.
Placental growth factor(PlGF) is a protein that in humans is encoded by the PGF gene.
Semaphorin-3A is a protein that in humans is encoded by the SEMA3A gene.
Vascular endothelial growth factor B also known as VEGF-B is a protein that, in humans, is encoded by the VEGF-B gene. VEGF-B is a growth factor that belongs to the vascular endothelial growth factor family, of which VEGF-A is the best-known member.
Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.
Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.
Neuroangiogenesis is the coordinated growth of nerves and blood vessels. The nervous and blood vessel systems share guidance cues and cell-surface receptors allowing for this synchronised growth. The term neuroangiogenesis only came into use in 2002 and the process was previously known as neurovascular patterning. The combination of neurogenesis and angiogenesis is an essential part of embryonic development and early life. It is thought to have a role in pathologies such as endometriosis, brain tumors, and Alzheimer's disease.
Nader Rahimi is a Molecular Biologist and is currently an Associate Professor at the Department of Pathology and Laboratory Medicine at Boston University.