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KDR (kinase insert domain receptor)/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2)

Written2015-10Noah Sorrelle, Rolf Brekken
University of Texas Southwestern Medical Center noah.sorrelle@utsouthwestern.edu, rolf.brekken@utsouthwestern.edu

Abstract This is a concise review of the KDR/VEGFR2 gene, including expression, function, and implications of VEGFR2 expression in cancer.

Keywords CD309, Kdr, Flk-1, VEGFR2, Angiogenesis, Vascular Endothelial Growth Factor Receptor 2, Tumor Angiogenesis

(Note : for Links provided by Atlas : click)

Identity

Alias_nameskinase insert domain receptor (a type III receptor tyrosine kinase)
Alias_symbol (synonym)FLK1
VEGFR
VEGFR2
CD309
Other aliasFlk1
HGNC (Hugo) KDR
LocusID (NCBI) 3791
Atlas_Id 41055
Location 4q12  [Link to chromosome band 4q12]
Location_base_pair Starts at 55078259 and ends at 55125595 bp from pter ( according to hg19-Feb_2009)  [Mapping KDR.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
KDR (4q12) / PDGFRA (4q12)

DNA/RNA

 
Description The human KDR/VEGFR2 gene was cloned in 1991 and mapped in 1992 (Terman BI et al., 1991, Terman BI et al., 1992). The human gene (Kdr/VEGFR2) maps to human chromosome 4. The mouse gene (Kdr/Vegfr2/Flk-1) was cloned in 1991(Matthews W et al., 1991). The mouse gene (Flk-1/Vegfr2) is located on mouse chromosome 5.
Transcription In humans, the KDR gene consists of 30 exons, spanning 47,337 bp of DNA on the reverse strand of Chromosome 4. Exon 1 contains 5' UTR and exon 30 contains 3' UTR. All 30 exons contain translated sequence. Three splice variants have been reported in Ensembl. Alternative splicing results in partial retention of intron 13 and an alternative stop codon, encoding a unique C-terminal sequence. Transcription factors regulating Vegfr2 expressing include ETS1 and ETS2 (Elvert G et al., 2003, Kappel A et al., 2000), EPAS1 (hypoxia inducible factor 2 alpha) (Elvert G et al., 2003), ETV2 (ER71/etsrp) (Lee D et al., 2008), and OVOL2 (Kim JY et al., 2014).

Protein

 
Description The canonical form of VEGFR2 comprises 1356 amino acids in humans and 1345 in mice. VEGFR2 is translated into a 150 kDa protein. Glycosylation of the extracellular domain results in the mature form at the cell surface which migrates at 230 kDa via western blot.
VEGFR2 is composed of three domains: an extracellular domain, transmembrane domain, and a cytosolic domain. The extracellular domain (including N-terminus) is composed of a signal peptide (aa: 1-20) and seven Ig-like subdomains (aa: 20-764). The second and third Ig-like subdomains (aa: 141-207, 224-320) facilitate binding of the principal VEGFR2 ligand, VEGFA (Fug G et al., 1998, Shinkai A et al., 1998). This is followed by a single-pass type I transmembrane domain (aa: 765-785).
The intracellular region (aa: 786-1356) consists of a juxtamembrane domain (JMD) and kinase domain. Biochemical analyses by Solowiej et al. (2009) determined that the JMD promotes autophosphorylation of the kinase domain, which is preceded by phosphorylation of the JMD residue, Y801(Solowiej J et al., 2009). Replacing the VEGFR2 JMD with the VEGFR1 JMD reduces the kinase activity of VEGFR2 in vitro. Conversely, replacing the VEGFR1 JMD with the VEGFR2 JMD increases the kinase activity of VEGFR1(Gille H et al., 2000). These data suggest that the higher kinase activity of VEGFR2 relative to VEGFR1 may be partially explained by differences in the JMD.
The kinase domain (KD; aa: 834-1162) is split by a 70 amino acid insert (aa: 930-1000). Phosphorylation of the KD activation loop residues Y1054 and Y1059 is required for kinase activity(Kendall RL et al., 1999). Additional phosphorylation sites in the intracellular domain facilitate specific interactions of between VEGFR2 and signaling mediators, including PLC gamma, SHB, SCK, SHCA, GRB2, son of sevenless (SOS), and NCK. For further review, see S. Koch and L. Claesson-Welsh, 2012, and Claesson-Welsh and Welsh, 2013 (Claesson-Welsh L et al., 2013, Koch S et al., 2012).
Co-receptors:
Integrins, neuropilin-1, and CD146 promote VEGFR2 activation, and mediate VEGFR2 activities, including endothelial cell migration, permeability, and angiogenesis. For more information, see Table 1 and Koch and Claesson-Welsh, 2012.
Alternative Isoforms:
In 2009, Albuquerque et al. discovered that alternative splicing produces a soluble form of VEGFR2, present in mouse and human cornea (Albuquerque RJ et al., 2009). This isoform results from inclusion of the intron following exon 13 and results in a truncated product which migrates at 75 kDa via western blot. This isoform contains only the extracellular domain of VEGFR2 and a unique C-terminal sequence. Characterization of sVEGFR2 revealed that it may play a role as an endogenous inhibitor of lymphoangiogenesis via antagonizing VEGF-C/VEGFR3 signaling (Albuquerque RJ et al., 2009).
Ligands:
VEGF-A (Terman BI et al., 1992), VEGF-C (Joukov V et al., 1996), VEGF-D (Achen MG et al., 1998), and VEGF-E (M Meyer et al., 1999, Ogawa S et al., 1998). VEGF-A is the primary endogenous ligand activating VEGFR2 signaling, while VEGF-C and VEGF-D signal mostly through VEGFR3. VEGF-E is encoded by the Orf virus and activates VEGFR2 similarly to VEGF-A. Unlike VEGF-A, however, VEGF-E is a VEGFR2-exclusive ligand.
 
Expression VEGFR2 is the principal VEGF receptor expressed on blood endothelial cells. Vegfr2-null mice die at E8.5 due to inadequate development of endothelial and hematopoietic cells(Shalaby F et al., 1995). Vegfr2 expression levels peak during embryonic angiogenesis and vasculogenesis(Millauer B et al., 1993, Oelrichs RB et al., 1993). In adults, VEGFR2 is expressed prominently on vascular endothelial cells, where it's expression is, in part, regulated by fibroblast growth factor signaling(Michael S. Pepper et al., 1998, Murakami M et al., 2011). Expression is also observed on hematopoietic stem cells and megakaryocytes(Casella I et al., 2003, Katoh O et al., 1995, Larrivée B et al., 2003).
Localisation Full length VEGFR2 is localized on the plasma membrane and is internalized in a VEGF binding-dependent manner(Koch S et al., 2012, Waltenberger J et al., 1994). Soluble VEGFR2 is secreted from the cell.
 
Function VEGFR2 is the premier receptor mediating VEGF-A activity on endothelial cells, where it functions to enhance proliferation, migration, and survival(Gerber HP et al., 1998, Jia H et al., 2004, Terman BI et al., 1992, Waltenberger J et al., 1994). Vegfr2 also promotes the survival of hematopoietic stem cells(Larrivée B et al., 2003).
VEGFR2 is the principal VEGF receptor involved in vascular angiogenesis and the regulation of vascular permeability(Kowanetz M et al., 2006, Terman BI et al., 1992). VEGFR2 activity on vascular endothelial cells in tumors promotes tumor angiogenesis(K. H. Plate et al., 1993, Millauer B et al., 1994). For the effects of VEGFR2 signaling on different cell types, see Table 2.
VEGF Signaling Inhibitors:
Strategies employed to target VEGF signaling are multifocal, consisting of monoclonal antibodies for both the ligands and VEGFRs, recombinant VEGFR extracellular domain fusion proteins (Table 3), and small molecule receptor tyrosine kinase inhibitors (Table 4)
 
 
 

Mutations

 
Somatic Increased VEGFR2 copy number has been identified in breast(Johansson I et al., 2012), non-small cell lung cancer (Yang F et al., 2011), and neurological malignancies (Blom T et al., 2010, Puputti M et al., 2006). Missense mutations have been identified in hemangioma, leading to constitutive activation of VEGFR2 (Antonescu CR et al., 2009, Jinnin M et al., 2008, Walter JW et al., 2002). Wang et al., 2007, identified that polymorphisms in the VEGFR2 were associated with coronary heart disease(Wang Y et al., 2007) (Table 5).
Glubb et al., 2011, characterized the significance of selected single nucleotide polymorphisms on VEGFR2 function and expression (Table 6). Of particular note, Glubb et al., 2011, identified that a SNP that results in the amino acid change Q472H, which was associated with increased VEGFR2 activity, and was correlated with increased microvessel density in non-small cell lung cancer patients (Glubb DM et al., 2011) (Table 6).

Implicated in

Note
  
Entity Various Cancers (see Table)
Note The expression VEGFR2 is increased by endothelial cells during tumor angiogenesis (K. H. Plate et al., 1993, Millauer B et al., 1994). VEGFR2 expression has also been identified on myeloid-derived suppressor cells, where it functions in splenic MDSC expansion and the chemotaxis of MDSCs into tumors (Dineen et al., 2008, Huang Y et al., 2007, Roland CL et al., 2009).
In addition to stromal cells, VEGFR2 expression by tumor cells has been identified in a variety of cancers, including bladder (Xia G et al., 2006), brain (Knizetova P et al., 2008, Nobusawa S1 et al., 2011, Puputti M et al., 2006, Yao X et al., 2013), breast (Ghosh S et al., 2008, Nakopoulou L et al., 2002, Yan JD et al., 2015), carcinoid (Silva SR et al., 2011), cervical (Longatto-Filho A et al., 2009), colon (Giatromanolaki A et al., 2007, Takahashi Y et al., 1995), endometrial ID: 5045> (Giatromanolaki A et al., 2006), esophageal (Gockel I et al., 2008), gastric (Ozdemir F et al., 2006), head and neck (Lalla RV et al., 2003, Neuchrist C et al., 2001), lung (Carrillo de Santa Pau E et al., 2009, Chatterjee S et al., 2013, Decaussin M et al., 1999, Seto T et al., 2006, Yang F et al., 2011), melanoma (Straume O et al., 2003), mesothelioma (Strizzi L et al., 2001), multiple myeloma (Giatromanolaki A et al., 2010), myeloid leukemia (Padró T et al., 2002), ovarian (Chen H et al., 2004, Spannuth WA et al., 2009), pancreatic (Chung GG et al., 2006, Itakura J et al., 2000, von Marschall Z et al., 2000), prostate (Jackson MW et al., 2002, Köllermann J et al., 2001), renal cell carcinoma (Badalian G et al., 2007), squamous (Sato H et al., 2009), and thyroid (Rodrèguez-Antona C et al., 2010), (Table 7).
In some cases, tumor cell expression of VEGFR2 appears to play an important function in tumor progression and correlates with worse prognosis. For example, Yang et al. (2011) identified VEGFR2 copy number gains (CNG) in 32% of tumors, which was associated with increased VEGFR2 protein, tumor angiogenesis, and correlated with poor prognosis(Yang F et al., 2011). Furthermore, Chatterjee et al. (2013) identified that the levels of VEGF/VEGFR2 binding on tumor cells strongly correlated with tumor angiogenesis, and selective VEGFR2 inhibition had a significant combinatorial effect with MEK inhibitors in reducing tumor growth in preclinical models of NSCLC(Chatterjee S et al., 2013).
Yan et al. (2015) found that VEGFR2 expression by breast tumor cells was significantly correlated with increased lymph node metastasis, epithelial to mesenchymal transition (EMT) marker expression, and reduced overall survival(Yan JD et al., 2015).
For further review of expression and function of VEGFR2 in different cancers, see Table 7 and Goel and Mercurio, 2013(Goel HL et al., 2013).
 
  
  
Entity Coronary Heart Disease
Note Wang et al., 2007, identified that polymorphisms in the VEGFR2 were associated with coronary heart disease (Wang Y et al., 2007) (Table 5).
  
  
Entity Hemangioma
Note Missense mutations have been identified in hemangioma, leading to constitutive activation of VEGFR2 (Antonescu CR et al., 2009, Jinnin M et al., 2008, Walter JW et al., 2002).
  

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Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts
Roland CL, Dineen SP, Lynn KD, Sullivan LA, Dellinger MT, Sadegh L, Sullivan JP, Shames DS, Brekken RA
Mol Cancer Ther 2009 Jul;8(7):1761-71
PMID 19567820
 
VEGFR2 expression and relationship between tumor neovascularization and histologic characteristics in oral squamous cell carcinoma
Sato H, Takeda Y
J Oral Sci 2009 Dec;51(4):551-7
PMID 20032607
 
Prognostic value of expression of vascular endothelial growth factor and its flt-1 and KDR receptors in stage I non-small-cell lung cancer
Seto T, Higashiyama M, Funai H, Imamura F, Uematsu K, Seki N, Eguchi K, Yamanaka T, Ichinose Y
Lung Cancer 2006 Jul;53(1):91-6
PMID 16697074
 
Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice
Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, Schuh AC
Nature 1995 Jul 6;376(6535):62-6
PMID 7596435
 
Mapping of the sites involved in ligand association and dissociation at the extracellular domain of the kinase insert domain-containing receptor for vascular endothelial growth factor
Shinkai A, Ito M, Anazawa H, Yamaguchi S, Shitara K, Shibuya M
J Biol Chem 1998 Nov 20;273(47):31283-8
PMID 9813036
 
VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis
Silva SR, Bowen KA, Rychahou PG, Jackson LN, Weiss HL, Lee EY, Townsend CM Jr, Evers BM
Int J Cancer 2011 Mar 1;128(5):1045-56
PMID 20473929
 
Characterizing the effects of the juxtamembrane domain on vascular endothelial growth factor receptor-2 enzymatic activity, autophosphorylation, and inhibition by axitinib
Solowiej J, Bergqvist S, McTigue MA, Marrone T, Quenzer T, Cobbs M, Ryan K, Kania RS, Diehl W, Murray BW
Biochemistry 2009 Jul 28;48(29):7019-31
PMID 19526984
 
Functional significance of VEGFR-2 on ovarian cancer cells
Spannuth WA, Nick AM, Jennings NB, Armaiz-Pena GN, Mangala LS, Danes CG, Lin YG, Merritt WM, Thaker PH, Kamat AA, Han LY, Tonra JR, Coleman RL, Ellis LM, Sood AK
Int J Cancer 2009 Mar 1;124(5):1045-53
PMID 19058181
 
Increased expression of VEGF-receptors (FLT-1, KDR, NRP-1) and thrombospondin-1 is associated with glomeruloid microvascular proliferation, an aggressive angiogenic phenotype, in malignant melanoma
Straume O, Akslen LA
Angiogenesis 2003;6(4):295-301
PMID 15166498
 
Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma
Strizzi L, Catalano A, Vianale G, Orecchia S, Casalini A, Tassi G, Puntoni R, Mutti L, Procopio A
J Pathol 2001 Apr;193(4):468-75
PMID 11276005
 
Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer
Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM
Cancer Res 1995 Sep 15;55(18):3964-8
PMID 7664263
 
Identification of a new endothelial cell growth factor receptor tyrosine kinase
Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB
Oncogene 1991 Sep;6(9):1677-83
PMID 1656371
 
Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor
Terman BI, Dougher-Vermazen M, Carrion ME, Dimitrov D, Armellino DC, Gospodarowicz D, Böhlen P
Biochem Biophys Res Commun 1992 Sep 30;187(3):1579-86
PMID 1417831
 
The KDR gene maps to human chromosome 4q31
Terman BI, Jani-Sait S, Carrion ME, Shows TB
2----q32, a locus which is distinct from locations for other type III growth factor receptor tyrosine kinases Cytogenet Cell Genet
PMID 1324138
 
Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor
Waltenberger J, Claesson-Welsh L, Siegbahn A, Shibuya M, Heldin CH
J Biol Chem 1994 Oct 28;269(43):26988-95
PMID 7929439
 
Somatic mutation of vascular endothelial growth factor receptors in juvenile hemangioma
Walter JW, North PE, Waner M, Mizeracki A, Blei F, Walker JW, Reinisch JF, Marchuk DA
Genes Chromosomes Cancer 2002 Mar;33(3):295-303
PMID 11807987
 
Polymorphisms of KDR gene are associated with coronary heart disease
Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R
J Am Coll Cardiol 2007 Aug 21;50(8):760-7
PMID 17707181
 
Expression and significance of vascular endothelial growth factor receptor 2 in bladder cancer
Xia G, Kumar SR, Hawes D, Cai J, Hassanieh L, Groshen S, Zhu S, Masood R, Quinn DI, Broek D, Stein JP, Gill PS
J Urol 2006 Apr;175(4):1245-52
PMID 16515971
 
Expression and prognostic significance of VEGFR-2 in breast cancer
Yan JD, Liu Y, Zhang ZY, Liu GY, Xu JH, Liu LY, Hu YM
Pathol Res Pract 2015 Jul;211(7):539-43
PMID 25976977
 
Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy
Yang F, Tang X, Riquelme E, Behrens C, Nilsson MB, Giri U, Varella-Garcia M, Byers LA, Lin HY, Wang J, Raso MG, Girard L, Coombes K, Lee JJ, Herbst RS, Minna JD, Heymach JV, Wistuba II
Cancer Res 2011 Aug 15;71(16):5512-21
PMID 21724587
 
Vascular endothelial growth factor receptor 2 (VEGFR-2) plays a key role in vasculogenic mimicry formation, neovascularization and tumor initiation by Glioma stem-like cells
Yao X, Ping Y, Liu Y, Chen K, Yoshimura T, Liu M, Gong W, Chen C, Niu Q, Guo D, Zhang X, Wang JM, Bian X
PLoS One 2013;8(3):e57188
PMID 23536763
 
De novo expression of vascular endothelial growth factor in human pancreatic cancer: evidence for an autocrine mitogenic loop
von Marschall Z, Cramer T, Höcker M, Burde R, Plath T, Schirner M, Heidenreich R, Breier G, Riecken EO, Wiedenmann B, Rosewicz S
Gastroenterology 2000 Nov;119(5):1358-72
PMID 11054395
 

Citation

This paper should be referenced as such :
Sorrelle N, Brekken R
KDR (kinase insert domain receptor)/Vascular Endothelial Growth Factor Receptor 2 (VEGFR2);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/KDRID41055ch4q12.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]
  Bone: Angiosarcoma
Breast: Ductal carcinoma
Bone: Vascular Tumors


External links

Nomenclature
HGNC (Hugo)KDR   6307
Cards
AtlasKDRID41055ch4q12
Entrez_Gene (NCBI)KDR  3791  kinase insert domain receptor
AliasesCD309; FLK1; VEGFR; VEGFR2
GeneCards (Weizmann)KDR
Ensembl hg19 (Hinxton)ENSG00000128052 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000128052 [Gene_View]  chr4:55078259-55125595 [Contig_View]  KDR [Vega]
ICGC DataPortalENSG00000128052
TCGA cBioPortalKDR
AceView (NCBI)KDR
Genatlas (Paris)KDR
WikiGenes3791
SOURCE (Princeton)KDR
Genetics Home Reference (NIH)KDR
Genomic and cartography
GoldenPath hg38 (UCSC)KDR  -     chr4:55078259-55125595 -  4q12   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)KDR  -     4q12   [Description]    (hg19-Feb_2009)
EnsemblKDR - 4q12 [CytoView hg19]  KDR - 4q12 [CytoView hg38]
Mapping of homologs : NCBIKDR [Mapview hg19]  KDR [Mapview hg38]
OMIM191306   602089   
Gene and transcription
Genbank (Entrez)AB209901 AF035121 AF063658 AK293668 BC131822
RefSeq transcript (Entrez)NM_002253
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)KDR
Cluster EST : UnigeneHs.479756 [ NCBI ]
CGAP (NCI)Hs.479756
Alternative Splicing GalleryENSG00000128052
Gene ExpressionKDR [ NCBI-GEO ]   KDR [ EBI - ARRAY_EXPRESS ]   KDR [ SEEK ]   KDR [ MEM ]
Gene Expression Viewer (FireBrowse)KDR [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3791
GTEX Portal (Tissue expression)KDR
Human Protein AtlasENSG00000128052-KDR [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP35968   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP35968  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP35968
Splice isoforms : SwissVarP35968
Catalytic activity : Enzyme2.7.10.1 [ Enzyme-Expasy ]   2.7.10.12.7.10.1 [ IntEnz-EBI ]   2.7.10.1 [ BRENDA ]   2.7.10.1 [ KEGG ]   
PhosPhoSitePlusP35968
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)    RECEPTOR_TYR_KIN_III (PS00240)   
Domains : Interpro (EBI)Ig-like_dom    Ig-like_fold    Ig_I-set    Ig_sub    Ig_sub2    Immunoglobulin    Kinase-like_dom    Prot_kinase_dom    Protein_kinase_ATP_BS    Ser-Thr/Tyr_kinase_cat_dom    Tyr_kinase_AS    Tyr_kinase_cat_dom    Tyr_kinase_rcpt_3_CS    VEGFR2_rcpt   
Domain families : Pfam (Sanger)I-set (PF07679)    ig (PF00047)    Pkinase_Tyr (PF07714)   
Domain families : Pfam (NCBI)pfam07679    pfam00047    pfam07714   
Domain families : Smart (EMBL)IG (SM00409)  IGc2 (SM00408)  TyrKc (SM00219)  
Conserved Domain (NCBI)KDR
DMDM Disease mutations3791
Blocks (Seattle)KDR
PDB (SRS)1VR2    1Y6A    1Y6B    1YWN    2M59    2MET    2MEU    2OH4    2P2H    2P2I    2QU5    2QU6    2RL5    2X1W    2X1X    2XIR    3B8Q    3B8R    3BE2    3C7Q    3CJF    3CJG    3CP9    3CPB    3CPC    3DTW    3EFL    3EWH    3KVQ    3S35    3S36    3S37    3U6J    3V2A    3V6B    3VHE    3VHK    3VID    3VNT    3VO3    3WZD    3WZE    4AG8    4AGC    4AGD    4ASD    4ASE    5EW3   
PDB (PDBSum)1VR2    1Y6A    1Y6B    1YWN    2M59    2MET    2MEU    2OH4    2P2H    2P2I    2QU5    2QU6    2RL5    2X1W    2X1X    2XIR    3B8Q    3B8R    3BE2    3C7Q    3CJF    3CJG    3CP9    3CPB    3CPC    3DTW    3EFL    3EWH    3KVQ    3S35    3S36    3S37    3U6J    3V2A    3V6B    3VHE    3VHK    3VID    3VNT    3VO3    3WZD    3WZE    4AG8    4AGC    4AGD    4ASD    4ASE    5EW3   
PDB (IMB)1VR2    1Y6A    1Y6B    1YWN    2M59    2MET    2MEU    2OH4    2P2H    2P2I    2QU5    2QU6    2RL5    2X1W    2X1X    2XIR    3B8Q    3B8R    3BE2    3C7Q    3CJF    3CJG    3CP9    3CPB    3CPC    3DTW    3EFL    3EWH    3KVQ    3S35    3S36    3S37    3U6J    3V2A    3V6B    3VHE    3VHK    3VID    3VNT    3VO3    3WZD    3WZE    4AG8    4AGC    4AGD    4ASD    4ASE    5EW3   
PDB (RSDB)1VR2    1Y6A    1Y6B    1YWN    2M59    2MET    2MEU    2OH4    2P2H    2P2I    2QU5    2QU6    2RL5    2X1W    2X1X    2XIR    3B8Q    3B8R    3BE2    3C7Q    3CJF    3CJG    3CP9    3CPB    3CPC    3DTW    3EFL    3EWH    3KVQ    3S35    3S36    3S37    3U6J    3V2A    3V6B    3VHE    3VHK    3VID    3VNT    3VO3    3WZD    3WZE    4AG8    4AGC    4AGD    4ASD    4ASE    5EW3   
Structural Biology KnowledgeBase1VR2    1Y6A    1Y6B    1YWN    2M59    2MET    2MEU    2OH4    2P2H    2P2I    2QU5    2QU6    2RL5    2X1W    2X1X    2XIR    3B8Q    3B8R    3BE2    3C7Q    3CJF    3CJG    3CP9    3CPB    3CPC    3DTW    3EFL    3EWH    3KVQ    3S35    3S36    3S37    3U6J    3V2A    3V6B    3VHE    3VHK    3VID    3VNT    3VO3    3WZD    3WZE    4AG8    4AGC    4AGD    4ASD    4ASE    5EW3   
SCOP (Structural Classification of Proteins)1VR2    1Y6A    1Y6B    1YWN    2M59    2MET    2MEU    2OH4    2P2H    2P2I    2QU5    2QU6    2RL5    2X1W    2X1X    2XIR    3B8Q    3B8R    3BE2    3C7Q    3CJF    3CJG    3CP9    3CPB    3CPC    3DTW    3EFL    3EWH    3KVQ    3S35    3S36    3S37    3U6J    3V2A    3V6B    3VHE    3VHK    3VID    3VNT    3VO3    3WZD    3WZE    4AG8    4AGC    4AGD    4ASD    4ASE    5EW3   
CATH (Classification of proteins structures)1VR2    1Y6A    1Y6B    1YWN    2M59    2MET    2MEU    2OH4    2P2H    2P2I    2QU5    2QU6    2RL5    2X1W    2X1X    2XIR    3B8Q    3B8R    3BE2    3C7Q    3CJF    3CJG    3CP9    3CPB    3CPC    3DTW    3EFL    3EWH    3KVQ    3S35    3S36    3S37    3U6J    3V2A    3V6B    3VHE    3VHK    3VID    3VNT    3VO3    3WZD    3WZE    4AG8    4AGC    4AGD    4ASD    4ASE    5EW3   
SuperfamilyP35968
Human Protein Atlas [tissue]ENSG00000128052-KDR [tissue]
Peptide AtlasP35968
HPRD01867
IPIIPI00021396   
Protein Interaction databases
DIP (DOE-UCLA)P35968
IntAct (EBI)P35968
FunCoupENSG00000128052
BioGRIDKDR
STRING (EMBL)KDR
ZODIACKDR
Ontologies - Pathways
QuickGOP35968
Ontology : AmiGOangiogenesis  vasculogenesis  positive regulation of protein phosphorylation  positive regulation of endothelial cell proliferation  cell migration involved in sprouting angiogenesis  endothelium development  protein tyrosine kinase activity  protein tyrosine kinase activity  transmembrane receptor protein tyrosine kinase activity  signal transducer, downstream of receptor, with protein tyrosine kinase activity  vascular endothelial growth factor-activated receptor activity  integrin binding  protein binding  ATP binding  extracellular region  nucleus  endosome  early endosome  endoplasmic reticulum  Golgi apparatus  plasma membrane  plasma membrane  plasma membrane  integral component of plasma membrane  transmembrane receptor protein tyrosine kinase signaling pathway  positive regulation of cell proliferation  positive regulation of cell proliferation  regulation of cell shape  positive regulation of endothelial cell migration  positive regulation of phosphatidylinositol 3-kinase signaling  viral process  positive regulation of macroautophagy  peptidyl-tyrosine phosphorylation  growth factor binding  signal transduction by protein phosphorylation  cell junction  extracellular matrix organization  positive regulation of cell migration  positive regulation of cell migration  embryonic hemopoiesis  calcium-mediated signaling using intracellular calcium source  cellular response to vascular endothelial growth factor stimulus  cellular response to vascular endothelial growth factor stimulus  positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway  peptidyl-tyrosine autophosphorylation  negative regulation of apoptotic process  positive regulation of MAPK cascade  membrane raft  positive regulation of angiogenesis  protein autophosphorylation  vascular endothelial growth factor receptor signaling pathway  vascular endothelial growth factor receptor signaling pathway  vascular endothelial growth factor receptor signaling pathway  positive regulation of positive chemotaxis  positive regulation of nitric-oxide synthase biosynthetic process  positive regulation of nitric-oxide synthase biosynthetic process  Hsp90 protein binding  positive regulation of focal adhesion assembly  positive regulation of mitochondrial depolarization  positive regulation of ERK1 and ERK2 cascade  positive regulation of mitochondrial fission  sorting endosome  negative regulation of endothelial cell apoptotic process  positive regulation of vasculogenesis  
Ontology : EGO-EBIangiogenesis  vasculogenesis  positive regulation of protein phosphorylation  positive regulation of endothelial cell proliferation  cell migration involved in sprouting angiogenesis  endothelium development  protein tyrosine kinase activity  protein tyrosine kinase activity  transmembrane receptor protein tyrosine kinase activity  signal transducer, downstream of receptor, with protein tyrosine kinase activity  vascular endothelial growth factor-activated receptor activity  integrin binding  protein binding  ATP binding  extracellular region  nucleus  endosome  early endosome  endoplasmic reticulum  Golgi apparatus  plasma membrane  plasma membrane  plasma membrane  integral component of plasma membrane  transmembrane receptor protein tyrosine kinase signaling pathway  positive regulation of cell proliferation  positive regulation of cell proliferation  regulation of cell shape  positive regulation of endothelial cell migration  positive regulation of phosphatidylinositol 3-kinase signaling  viral process  positive regulation of macroautophagy  peptidyl-tyrosine phosphorylation  growth factor binding  signal transduction by protein phosphorylation  cell junction  extracellular matrix organization  positive regulation of cell migration  positive regulation of cell migration  embryonic hemopoiesis  calcium-mediated signaling using intracellular calcium source  cellular response to vascular endothelial growth factor stimulus  cellular response to vascular endothelial growth factor stimulus  positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway  peptidyl-tyrosine autophosphorylation  negative regulation of apoptotic process  positive regulation of MAPK cascade  membrane raft  positive regulation of angiogenesis  protein autophosphorylation  vascular endothelial growth factor receptor signaling pathway  vascular endothelial growth factor receptor signaling pathway  vascular endothelial growth factor receptor signaling pathway  positive regulation of positive chemotaxis  positive regulation of nitric-oxide synthase biosynthetic process  positive regulation of nitric-oxide synthase biosynthetic process  Hsp90 protein binding  positive regulation of focal adhesion assembly  positive regulation of mitochondrial depolarization  positive regulation of ERK1 and ERK2 cascade  positive regulation of mitochondrial fission  sorting endosome  negative regulation of endothelial cell apoptotic process  positive regulation of vasculogenesis  
Pathways : BIOCARTAVEGF, Hypoxia, and Angiogenesis [Genes]    Actions of Nitric Oxide in the Heart [Genes]   
Pathways : KEGG   
REACTOMEP35968 [protein]
REACTOME PathwaysR-HSA-5218921 [pathway]   
NDEx NetworkKDR
Atlas of Cancer Signalling NetworkKDR
Wikipedia pathwaysKDR
Orthology - Evolution
OrthoDB3791
GeneTree (enSembl)ENSG00000128052
Phylogenetic Trees/Animal Genes : TreeFamKDR
HOVERGENP35968
HOGENOMP35968
Homologs : HomoloGeneKDR
Homology/Alignments : Family Browser (UCSC)KDR
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKDR [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KDR
dbVarKDR
ClinVarKDR
1000_GenomesKDR 
Exome Variant ServerKDR
ExAC (Exome Aggregation Consortium)ENSG00000128052
GNOMAD BrowserENSG00000128052
Genetic variants : HAPMAP3791
Genomic Variants (DGV)KDR [DGVbeta]
DECIPHERKDR [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisKDR 
Mutations
ICGC Data PortalKDR 
TCGA Data PortalKDR 
Broad Tumor PortalKDR
OASIS PortalKDR [ Somatic mutations - Copy number]
Cancer Gene: CensusKDR 
Somatic Mutations in Cancer : COSMICKDR  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDKDR
intOGen PortalKDR
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)The Globin Gene Server
BioMutasearch KDR
DgiDB (Drug Gene Interaction Database)KDR
DoCM (Curated mutations)KDR (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KDR (select a term)
intoGenKDR
NCG5 (London)KDR
Cancer3DKDR(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM191306    602089   
Orphanet
MedgenKDR
Genetic Testing Registry KDR
NextProtP35968 [Medical]
TSGene3791
GENETestsKDR
Target ValidationKDR
Huge Navigator KDR [HugePedia]
snp3D : Map Gene to Disease3791
BioCentury BCIQKDR
ClinGenKDR
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3791
Chemical/Pharm GKB GenePA30086
Drug Sensitivity KDR
Clinical trialKDR
Miscellaneous
canSAR (ICR)KDR (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineKDR
EVEXKDR
GoPubMedKDR
iHOPKDR
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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