KDR

Official Full Name

kinase insert domain receptor

Organism

Homo sapiens

GeneID

3791

Background

Vascular endothelial growth factor (VEGF) is a major growth factor for endothelial cells. This gene encodes one of the two receptors of the VEGF. This receptor, known as kinase insert domain receptor, is a type III receptor tyrosine kinase. It functions as the main mediator of VEGF-induced endothelial proliferation, survival, migration, tubular morphogenesis and sprouting. The signalling and trafficking of this receptor are regulated by multiple factors, including Rab GTPase, P2Y purine nucleotide receptor, integrin alphaVbeta3, T-cell protein tyrosine phosphatase, etc.. Mutations of this gene are implicated in infantile capillary hemangiomas. [provided by RefSeq, May 2009]

Synonyms

FLK1; CD309; VEGFR; VEGFR2;

Bio Chemical Class

mRNA target

Protein Sequence

MQSKVLLAVALWLCVETRAASVGLPSVSLDLPRLSIQKDILTIKANTTLQITCRGQRDLDWLWPNNQSGSEQRVEVTECSDGLFCKTLTIPKVIGNDTGAYKCFYRETDLASVIYVYVQDYRSPFIASVSDQHGVVYITENKNKTVVIPCLGSISNLNVSLCARYPEKRFVPDGNRISWDSKKGFTIPSYMISYAGMVFCEAKINDESYQSIMYIVVVVGYRIYDVVLSPSHGIELSVGEKLVLNCTARTELNVGIDFNWEYPSSKHQHKKLVNRDLKTQSGSEMKKFLSTLTIDGVTRSDQGLYTCAASSGLMTKKNSTFVRVHEKPFVAFGSGMESLVEATVGERVRIPAKYLGYPPPEIKWYKNGIPLESNHTIKAGHVLTIMEVSERDTGNYTVILTNPISKEKQSHVVSLVVYVPPQIGEKSLISPVDSYQYGTTQTLTCTVYAIPPPHHIHWYWQLEEECANEPSQAVSVTNPYPCEEWRSVEDFQGGNKIEVNKNQFALIEGKNKTVSTLVIQAANVSALYKCEAVNKVGRGERVISFHVTRGPEITLQPDMQPTEQESVSLWCTADRSTFENLTWYKLGPQPLPIHVGELPTPVCKNLDTLWKLNATMFSNSTNDILIMELKNASLQDQGDYVCLAQDRKTKKRHCVVRQLTVLERVAPTITGNLENQTTSIGESIEVSCTASGNPPPQIMWFKDNETLVEDSGIVLKDGNRNLTIRRVRKEDEGLYTCQACSVLGCAKVEAFFIIEGAQEKTNLEIIILVGTAVIAMFFWLLLVIILRTVKRANGGELKTGYLSIVMDPDELPLDEHCERLPYDASKWEFPRDRLKLGKPLGRGAFGQVIEADAFGIDKTATCRTVAVKMLKEGATHSEHRALMSELKILIHIGHHLNVVNLLGACTKPGGPLMVIVEFCKFGNLSTYLRSKRNEFVPYKTKGARFRQGKDYVGAIPVDLKRRLDSITSSQSSASSGFVEEKSLSDVEEEEAPEDLYKDFLTLEHLICYSFQVAKGMEFLASRKCIHRDLAARNILLSEKNVVKICDFGLARDIYKDPDYVRKGDARLPLKWMAPETIFDRVYTIQSDVWSFGVLLWEIFSLGASPYPGVKIDEEFCRRLKEGTRMRAPDYTTPEMYQTMLDCWHGEPSQRPTFSELVEHLGNLLQANAQQDGKDYIVLPISETLSMEEDSGLSLPTSPVSCMEEEEVCDPKFHYDNTAGISQYLQNSKRKSRPVSVKTFEDIPLEEPEVKVIPDDNQTDSGMVLASEELKTLEDRTKLSPSFGGMVPSKSRESVASEGSNQTSGYQSGYHSDDTDTTVYSSEEAELLKLIEIGVQTGSTAQILQPDSGTTLSSPPV

Open

Disease

Degenerative high myopia

Approved Drug

12 +

Clinical Trial Drug

35 +

Discontinued Drug

6 +

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Detailed Information

Vascular endothelial growth factor (VEGF) is a prime regulator of normal and tumor angiogenesis as well as vasculogenesis. VEGF is expressed in glioma cells and its receptors (Flt-1 and KDR) are expressed in the same glioma. These two receptors are tyrosine kinases and have an extracellular domain comprising seven immunoglobulin-like loops and a split tyrosine kinase domain. KDR is a receptor for various VEGF isoforms and VEGF-C; Flt-1 is a receptor for various isoforms.

VEGF is a covalent dimer and part of the mechanism that causes KDR dimerization is by simultaneously binding two receptor monomers. VEGF is expressed as five alternatively spliced isoforms, whereas VEGF165 does not bind to VEGF121, and KDR requires two additional cell surface molecules; these are heparan sulfate proteoglycan (HSPG) and neuropilin-1. The role of VEGF in stimulating KDR activation is more complicated than simply allowing the receptor monomers to be in intimate contact with each other. In addition to ligand binding regions within the extracellular domain of KDR, there are also regions that act to prevent VEGF-independent dimerization and thus unwanted signaling events.

Expression of the VEGF receptor type occurs in adult endothelial cells, including human umbilical vein endothelial cells, and some findings indicate that KDR mediates mitogenic and chemotactic effects of VEGF. Binding of VEGF to KDR stimulates other cellular responses, including enhanced expression of matrix degrading enzymes, inhibition of apoptosis, and regulation of nitric oxide synthase expression. KDR has a strong ligand-dependent tyrosine phosphorylation process in intact cells, and its main function is to mediate the proliferation and differentiation of endothelial cells. As a surface receptor, it can up-regulate the expression of VEGF and induce tumor angiogenesis, and is the main functional receptor of VEGF. VEGF mainly plays its role in promoting endothelial cell division and angiogenesis through KDR, and at the same time participates in promoting the invasive growth of glioma.

In general, the renewal of vascular endothelial cells is slow, while the proliferation of endothelial cells in tumor tissues are active, and KDR is highly expressed to mediate the generation of vascular endothelial growth factor in tumor angiogenesis. KDR siRNA can significantly silence KDR gene and protein expression in A549 cells (Human non-small cell lung cancer cells), inhibit the proliferation of A549 cells, and affect the growth rate of A549 cells; in combination with erlotinib, there is a synergistic effect, which can enhance the chemosensitivity of A549 cells to erlotinib.

KDR-positive cells participate in the development of mesoderm cells and, at the same time, differentiate into mature cardiomyocytes. Studies have shown that KDR-positive cells in isolated CDCs form cell aggregates that can further form cardiomyocyte-like cell structures. Once formed, KDR-positive cells can differentiate into two types of cardiovascular cells: one that migrates outward from the cell aggregate and forms a tubular morphology resembling a vascular tissue; one is that some cells differentiate into myocardial precursor cells and develop into maturity Cardiomyocytes. The dual biological characteristics of KDR-positive cells can largely satisfy the necessary conditions for donor cells to participate in myocardial repair, namely, induction of angiogenesis and myocardial regeneration in ischemic necrotic myocardial tissue.

References:

Marek C , et al. Cyclin I mRNA expression correlates with kinase insert domain receptor expression in human epithelial ovarian cancer. Anticancer Research, 2015, 35(2):1115-9.
Manni S , et al. Functional and structural characterization of the kinase insert and the carboxy terminal domain in VEGF receptor 2 activation. Faseb Journal Official Publication of the Federation of American Societies for Experimental Biology, 2014, 28(11):4914-23.
Wang J , et al. Discovery of vascular endothelial growth factor receptor tyrosine kinase inhibitors by quantitative structure–activity relationships, molecular dynamics simulation and free energy calculation. Rsc Advances, 2016, 6(42):35402-35415.
Nakanishi Y , et al. The Fibroblast Growth Factor Receptor Genetic Status as a Potential Predictor of the Sensitivity to CH5183284/Debio 1347, a Novel Selective FGFR Inhibitor. Molecular Cancer Therapeutics, 2014, 13(11):2547-2558.
Zhao S , et al. Differential regulation of orphan nuclear receptor TR3 transcript variants by novel vascular growth factor signaling pathways. The FASEB Journal, 2014, 28(10):4524-4533.

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