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Details on Person UniProt:P35968 KDR
| Class:Id | ReferenceGeneProduct:67174 |
|---|---|
| _chainChangeLog | signal peptide:1-19 added on Fri February 6 2015;chain:20-1356 added on Fri February 6 2015 |
| _displayName | UniProt:P35968 KDR |
| _timestamp | 2025-02-21 20:16:01 |
| chain | signal peptide:1-19 chain:20-1356 |
| checksum | 59E7C44B05CFEBB3 |
| comment | FUNCTION Tyrosine-protein kinase that acts as a cell-surface receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in the regulation of angiogenesis, vascular development, vascular permeability, and embryonic hematopoiesis. Promotes proliferation, survival, migration and differentiation of endothelial cells. Promotes reorganization of the actin cytoskeleton. Isoforms lacking a transmembrane domain, such as isoform 2 and isoform 3, may function as decoy receptors for VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount of free VEGFA and/or VEGFC and preventing their binding to FLT4. Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding of vascular growth factors to isoform 1 leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate and the activation of protein kinase C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Mediates phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, reorganization of the actin cytoskeleton and activation of PTK2/FAK1. Required for VEGFA-mediated induction of NOS2 and NOS3, leading to the production of the signaling molecule nitric oxide (NO) by endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.CATALYTIC ACTIVITY L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+)ACTIVITY REGULATION Present in an inactive conformation in the absence of bound ligand. Binding of VEGFA, VEGFC or VEGFD leads to dimerization and activation by autophosphorylation on tyrosine residues. Inhibited by the small molecule PTK inhibitor SU5614 ((3Z)-5-Chloro-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-2H-indol-2-one). May be regulated by hydrogen sulfide (H(2)S) levels via a H(2)S-sensitive intracellular disulfide bond.SUBUNIT Homodimer in the presence of bound dimeric VEGFA, VEGFC or VEGFD ligands; monomeric in the absence of bound ligands. Can also form heterodimers with FLT1/VEGFR1 and KDR/VEGFR2. Interacts (tyrosine phosphorylated) with LFYN, NCK1, PLCG1. Interacts (tyrosine-phosphorylated active form preferentially) with DAB2IP (via C2 domain and active form preferentially); the interaction occurs at the late phase of VEGFA response and inhibits KDR/VEGFR2 activity. Interacts with SHBSH2D2A/TSAD, GRB2, MYOF, CBL and PDCD6. Interacts (via C-terminus domain) with ERN1 (via kinase domain); the interaction is facilitated in a XBP1 isoform 1- and vascular endothelial growth factor (VEGF)-dependent manner in endothelial cells (PubMed:23529610). Interacts (via juxtamembrane region) with chaperone PDCL3 (via thioredoxin fold region); the interaction leads to increased KDR/VEGFR2 abundance through inhibition of its ubiquitination and degradation (PubMed:23792958, PubMed:26059764). Interacts (tyrosine phosphorylated) with CCDC88A/GIV (via SH2-like region); binding requires autophosphorylation of the KDR/VEGFR2 C-terminal region (PubMed:25187647). Interacts with isoform 2 of BSG (PubMed:25825981). Interacts with SLC31A1; this interaction is induced upon VEGFA stimulation leading to SLC31A1 and KDR subsequent co-internalization to early endosomes, thereby activating KDR downstream signaling in endothelial cells (PubMed:35027734).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.INTERACTION Localized with RAP1A at cell-cell junctions (By similarity). Colocalizes with ERN1 and XBP1 in the endoplasmic reticulum in endothelial cells in a vascular endothelial growth factor (VEGF)-dependent manner (PubMed:23529610).SUBCELLULAR LOCATION Detected on caveolae-enriched lipid rafts at the cell surface. Is recycled from the plasma membrane to endosomes and back again. Phosphorylation triggered by VEGFA binding promotes internalization and subsequent degradation. VEGFA binding triggers internalization and translocation to the nucleus.SUBCELLULAR LOCATION Detected in cornea (at protein level). Widely expressed.DOMAIN The second and third Ig-like C2-type (immunoglobulin-like) domains are sufficient for VEGFC binding.PTM N-glycosylated.PTM Ubiquitinated. Tyrosine phosphorylation of the receptor promotes its poly-ubiquitination, leading to its degradation via the proteasome or lysosomal proteases.PTM Autophosphorylated on tyrosine residues upon ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-951 is important for interaction with SH2D2A/TSAD and VEGFA-mediated reorganization of the actin cytoskeleton. Phosphorylation at Tyr-1175 is important for interaction with PLCG1 and SHB. Phosphorylation at Tyr-1214 is important for interaction with NCK1 and FYN. Dephosphorylated by PTPRB. Dephosphorylated by PTPRJ at Tyr-951, Tyr-996, Tyr-1054, Tyr-1059, Tyr-1175 and Tyr-1214.PTM The inhibitory disulfide bond between Cys-1024 and Cys-1045 may serve as a specific molecular switch for H(2)S-induced modification that regulates KDR/VEGFR2 function.DISEASE Disease susceptibility is associated with variants affecting the gene represented in this entry.DISEASE Plays a major role in tumor angiogenesis. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. |
| description | recommendedName: fullName evidence="57"Vascular endothelial growth factor receptor 2 shortName: VEGFR-2 ecNumber evidence="8 9"2.7.10.1 alternativeName: Fetal liver kinase 1 shortName: FLK-1 alternativeName: Kinase insert domain receptor shortName: KDR alternativeName: Protein-tyrosine kinase receptor flk-1 cdAntigenNameCD309/cdAntigenName |
| geneName | KDR FLK1 VEGFR2 |
| identifier | P35968 |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Alternative splicing Angiogenesis ATP-binding Cell junction Cell membrane Cytoplasm Cytoplasmic vesicle Developmental protein Differentiation Disulfide bond Endoplasmic reticulum Endosome Glycoprotein Host-virus interaction Immunoglobulin domain Kinase Membrane Nucleotide-binding Nucleus Phosphoprotein Proteomics identification Receptor Reference proteome Repeat Secreted Signal Transferase Transmembrane Transmembrane helix Tyrosine-protein kinase Ubl conjugation |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 |
| name | KDR |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:2888903] ENSEMBL:ENSG00000128052 KDR [Homo sapiens] |
| secondaryIdentifier | VGFR2_HUMAN A2RRS0 B5A925 C5IFA0 O60723 Q14178 |
| sequenceLength | 1356 |
| species | [Species:48887] Homo sapiens |
| (isoformParent) | [ReferenceIsoform:8975404] UniProt:P35968-1 KDR [Homo sapiens] [ReferenceIsoform:8975405] UniProt:P35968-2 KDR [Homo sapiens] [ReferenceIsoform:8975406] UniProt:P35968-3 KDR [Homo sapiens] |
| (referenceEntity) | [EntityWithAccessionedSequence:195382] VEGFR2 [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:4420103] p-6Y-VEGFR2 [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:8961271] KDR [extracellular region] [Homo sapiens] [EntityWithAccessionedSequence:9673613] VEGFR2(20-662)insVAGTWTSGLMSL-PDGFRA(471-1089) fusion [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9673636] p-11Y-VEGFR2(20-662)insVAGTWTSGLMSL-PDGFRA(471-1089) [plasma membrane] [Homo sapiens] [EntityWithAccessionedSequence:9860484] p-Y801,Y1054,Y1175-KDR [plasma membrane] [Homo sapiens] |
| (referenceSequence) | [ModifiedResidue:4420116] O4'-phospho-L-tyrosine at 1054 [ModifiedResidue:4420155] O4'-phospho-L-tyrosine at 1059 [ModifiedResidue:4420177] O4'-phospho-L-tyrosine at 951 [ModifiedResidue:4420188] O4'-phospho-L-tyrosine at 1214 [ModifiedResidue:4420205] O4'-phospho-L-tyrosine at 1175 [ModifiedResidue:5218751] O4'-phospho-L-tyrosine at 801 [FragmentReplacedModification:9673615] Replacement of residues 662 to 662 by LVAGTWTSGLMSL |
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No pathways have been reviewed or authored by UniProt:P35968 KDR (67174)
