ID VGFR2_HUMAN Reviewed; 1356 AA.
AC P35968; A2RRS0; B5A925; C5IFA0; O60723; Q14178;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 2.
DT 01-MAY-2013, entry version 154.
DE RecName: Full=Vascular endothelial growth factor receptor 2;
DE Short=VEGFR-2;
DE EC=2.7.10.1;
DE AltName: Full=Fetal liver kinase 1;
DE Short=FLK-1;
DE AltName: Full=Kinase insert domain receptor;
DE Short=KDR;
DE AltName: Full=Protein-tyrosine kinase receptor flk-1;
DE AltName: CD_antigen=CD309;
DE Flags: Precursor;
GN Name=KDR; Synonyms=FLK1, VEGFR2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), INTERACTION WITH VEGFC, AND
RP SUBCELLULAR LOCATION.
RX PubMed=18593464; DOI=10.1186/ar2447;
RA Jin P., Zhang J., Sumariwalla P.F., Ni I., Jorgensen B., Crawford D.,
RA Phillips S., Feldmann M., Shepard H.M., Paleolog E.M.;
RT "Novel splice variants derived from the receptor tyrosine kinase
RT superfamily are potential therapeutics for rheumatoid arthritis.";
RL Arthritis Res. Ther. 10:R73-R73(2008).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION IN INHIBITION OF
RP LYMPHANGIOGENESIS, INTERACTION WITH VEGFC, AND TISSUE SPECIFICITY.
RX PubMed=19668192; DOI=10.1038/nm.2018;
RA Albuquerque R.J., Hayashi T., Cho W.G., Kleinman M.E., Dridi S.,
RA Takeda A., Baffi J.Z., Yamada K., Kaneko H., Green M.G., Chappell J.,
RA Wilting J., Weich H.A., Yamagami S., Amano S., Mizuki N.,
RA Alexander J.S., Peterson M.L., Brekken R.A., Hirashima M., Capoor S.,
RA Usui T., Ambati B.K., Ambati J.;
RT "Alternatively spliced vascular endothelial growth factor receptor-2
RT is an essential endogenous inhibitor of lymphatic vessel growth.";
RL Nat. Med. 15:1023-1030(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Yin L.Y., Wu Y., Patterson C.;
RT "Full length human KDR/flk-1 sequence.";
RL Submitted (DEC-1997) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Umbilical vein;
RA Yu Y., Whitney R.G., Sato J.D.;
RT "Coding region for human VEGF receptor KDR (VEGFR-2).";
RL Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP HIS-472.
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-1356 (ISOFORM 1), AND VARIANT GLU-848.
RC TISSUE=Umbilical vein;
RX PubMed=1656371;
RA Terman B.I., Carrion M.E., Kovacs E., Rasmussen B.A., Eddy R.L.,
RA Shows T.B.;
RT "Identification of a new endothelial cell growth factor receptor
RT tyrosine kinase.";
RL Oncogene 6:1677-1683(1991).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22.
RX PubMed=7559454; DOI=10.1074/jbc.270.39.23111;
RA Patterson C., Perrella M.A., Hsieh C.-M., Yoshizumi M., Lee M.-E.,
RA Harber E.;
RT "Cloning and functional analysis of the promoter for KDR/flk-1, a
RT receptor for vascular endothelial growth factor.";
RL J. Biol. Chem. 270:23111-23118(1995).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH VEGFA.
RX PubMed=1417831; DOI=10.1016/0006-291X(92)90483-2;
RA Terman B.I., Dougher-Vermazen M., Carrion M.E., Dimitrov D.,
RA Armellino D.C., Gospodarowicz D., Boehlen P.;
RT "Identification of the KDR tyrosine kinase as a receptor for vascular
RT endothelial cell growth factor.";
RL Biochem. Biophys. Res. Commun. 187:1579-1586(1992).
RN [10]
RP FUNCTION AS VEGFA RECEPTOR; IN REGULATION OF CELL SHAPE; ACTIN
RP CYTOSKELETON REORGANIZATION; CELL MIGRATION AND CELL PROLIFERATION,
RP AND AUTOPHOSPHORYLATION.
RX PubMed=7929439;
RA Waltenberger J., Claesson-Welsh L., Siegbahn A., Shibuya M.,
RA Heldin C.H.;
RT "Different signal transduction properties of KDR and Flt1, two
RT receptors for vascular endothelial growth factor.";
RL J. Biol. Chem. 269:26988-26995(1994).
RN [11]
RP FUNCTION IN VEGFA SIGNALING; PHOSPHORYLATION OF PLCG1; ACTIVATION OF
RP MAP KINASES AND IN PROMOTING PROLIFERATION OF ENDOTHELIAL CELLS,
RP INTERACTION WITH VEGFA AND PLCG1, AUTOPHOSPHORYLATION, SUBCELLULAR
RP LOCATION, AND GLYCOSYLATION.
RX PubMed=9160888; DOI=10.1038/sj.onc.1201047;
RA Takahashi T., Shibuya M.;
RT "The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the
RT PLC-gamma pathway and partially induces mitotic signals in NIH3T3
RT fibroblasts.";
RL Oncogene 14:2079-2089(1997).
RN [12]
RP FUNCTION IN INDUCTION OF NOS2 AND NOS3.
RX PubMed=9837777; DOI=10.1006/bbrc.1998.9719;
RA Kroll J., Waltenberger J.;
RT "VEGF-A induces expression of eNOS and iNOS in endothelial cells via
RT VEGF receptor-2 (KDR).";
RL Biochem. Biophys. Res. Commun. 252:743-746(1998).
RN [13]
RP FUNCTION IN ACTIVATION OF THE PHOSPHATIDYLINOSITOL 3-KINASE AND AKT1
RP SIGNALING PATHWAY.
RX PubMed=9804796; DOI=10.1074/jbc.273.46.30336;
RA Gerber H.P., McMurtrey A., Kowalski J., Yan M., Keyt B.A., Dixit V.,
RA Ferrara N.;
RT "Vascular endothelial growth factor regulates endothelial cell
RT survival through the phosphatidylinositol 3'-kinase/Akt signal
RT transduction pathway. Requirement for Flk-1/KDR activation.";
RL J. Biol. Chem. 273:30336-30343(1998).
RN [14]
RP FUNCTION IN NITRIC OXIDE RELEASE.
RX PubMed=10600473; DOI=10.1006/bbrc.1999.1729;
RA Kroll J., Waltenberger J.;
RT "A novel function of VEGF receptor-2 (KDR): rapid release of nitric
RT oxide in response to VEGF-A stimulation in endothelial cells.";
RL Biochem. Biophys. Res. Commun. 265:636-639(1999).
RN [15]
RP CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT GLU-848,
RP PHOSPHORYLATION AT TYR-1054 AND TYR-1059, AND ENZYME REGULATION.
RX PubMed=10037737; DOI=10.1074/jbc.274.10.6453;
RA Kendall R.L., Rutledge R.Z., Mao X., Tebben A.J., Hungate R.W.,
RA Thomas K.A.;
RT "Vascular endothelial growth factor receptor KDR tyrosine kinase
RT activity is increased by autophosphorylation of two activation loop
RT tyrosine residues.";
RL J. Biol. Chem. 274:6453-6460(1999).
RN [16]
RP FUNCTION IN PHOSPHORYLATION OF PLCG1 AND PTK2/FAK1, INTERACTION WITH
RP VEGFA, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-996; TYR-1054 AND
RP TYR-1059, MUTAGENESIS OF TYR-996; TYR-1054 AND TYR-1059, SUBCELLULAR
RP LOCATION, AND ENZYME REGULATION.
RX PubMed=10102632; DOI=10.1038/sj.onc.1202478;
RA Dougher M., Terman B.I.;
RT "Autophosphorylation of KDR in the kinase domain is required for
RT maximal VEGF-stimulated kinase activity and receptor
RT internalization.";
RL Oncogene 18:1619-1627(1999).
RN [17]
RP INTERACTION WITH HIV-1 TAT.
RX PubMed=10590123; DOI=10.1128/JVI.74.1.344-353.2000;
RA Mitola S., Soldi R., Zanon I., Barra L., Gutierrez M.I., Berkhout B.,
RA Giacca M., Bussolino F.;
RT "Identification of specific molecular structures of human
RT immunodeficiency virus type 1 Tat relevant for its biological effects
RT on vascular endothelial cells.";
RL J. Virol. 74:344-353(2000).
RN [18]
RP FUNCTION IN ENDOTHELIAL CELL PROLIFERATION; PHOSPHORYLATION OF PLCG1
RP AND ACTIVATION OF MAP KINASES, PHOSPHORYLATION AT TYR-1175 AND
RP TYR-1214, AND MUTAGENESIS OF LYS-868 AND TYR-1175.
RX PubMed=11387210; DOI=10.1093/emboj/20.11.2768;
RA Takahashi T., Yamaguchi S., Chida K., Shibuya M.;
RT "A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-
RT A-dependent activation of PLC-gamma and DNA synthesis in vascular
RT endothelial cells.";
RL EMBO J. 20:2768-2778(2001).
RN [19]
RP UBIQUITINATION, FUNCTION IN NITRIC OXIDE PRODUCTION, SUBCELLULAR
RP LOCATION, AND INTERACTION WITH CBL.
RX PubMed=12649282; DOI=10.1074/jbc.M301410200;
RA Duval M., Bedard-Goulet S., Delisle C., Gratton J.P.;
RT "Vascular endothelial growth factor-dependent down-regulation of Flk-
RT 1/KDR involves Cbl-mediated ubiquitination. Consequences on nitric
RT oxide production from endothelial cells.";
RL J. Biol. Chem. 278:20091-20097(2003).
RN [20]
RP INTERACTION WITH FLT4.
RX PubMed=12881528; DOI=10.1074/jbc.M304499200;
RA Dixelius J., Makinen T., Wirzenius M., Karkkainen M.J., Wernstedt C.,
RA Alitalo K., Claesson-Welsh L.;
RT "Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-
RT 3) heterodimerization with VEGFR-2 in primary lymphatic endothelial
RT cells regulates tyrosine phosphorylation sites.";
RL J. Biol. Chem. 278:40973-40979(2003).
RN [21]
RP INTERACTION WITH SHB, AND FUNCTION IN CELL MIGRATION.
RX PubMed=15026417; DOI=10.1074/jbc.M312729200;
RA Holmqvist K., Cross M.J., Rolny C., Haegerkvist R., Rahimi N.,
RA Matsumoto T., Claesson-Welsh L., Welsh M.;
RT "The adaptor protein shb binds to tyrosine 1175 in vascular
RT endothelial growth factor (VEGF) receptor-2 and regulates VEGF-
RT dependent cellular migration.";
RL J. Biol. Chem. 279:22267-22275(2004).
RN [22]
RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION.
RX PubMed=14991896; DOI=10.1002/path.1520;
RA Fox S.B., Turley H., Cheale M., Blazquez C., Roberts H., James N.,
RA Cook N., Harris A., Gatter K.;
RT "Phosphorylated KDR is expressed in the neoplastic and stromal
RT elements of human renal tumours and shuttles from cell membrane to
RT nucleus.";
RL J. Pathol. 202:313-320(2004).
RN [23]
RP INTERACTION WITH VEGFA AND VEGFD, PHOSPHORYLATION AT TYR-1054 AND
RP TYR-1059, FUNCTION IN VEGFA AND VEGFD SIGNALING; ACTIVATION OF
RP MAPK1/ERK2 AND MAPK3/ERK1; ACTIVATION OF AKT1; PHOSPHORYLATION OF
RP PLCG1 AND NOS3; MODULATION OF INTRACELLULAR CA(2+) LEVELS; CELL
RP SURVIVAL AND POSITIVE REGULATION OF CELL PROLIFERATION; CELL MIGRATION
RP AND ANGIOGENESIS, AND ENZYME REGULATION.
RX PubMed=15215251; DOI=10.1074/jbc.M401538200;
RA Jia H., Bagherzadeh A., Bicknell R., Duchen M.R., Liu D., Zachary I.;
RT "Vascular endothelial growth factor (VEGF)-D and VEGF-A differentially
RT regulate KDR-mediated signaling and biological function in vascular
RT endothelial cells.";
RL J. Biol. Chem. 279:36148-36157(2004).
RN [24]
RP FUNCTION IN CELL MIGRATION; PHOSPHORYLATION OF PLCG1; ACTIVATION OF
RP MAPK1/ERK2; MAPK3/ERK1 AND THE MAP KINASES AND IN REGULATION OF ACTIN
RP CYTOSKELETON REORGANIZATION, INTERACTION WITH SH2D2A/TSAD,
RP PHOSPHORYLATION AT TYR-951; TYR-1054; TYR-1059; TYR-1214; TYR-1305;
RP TYR-1309 AND TYR-1319, AND MUTAGENESIS OF TYR-951.
RX PubMed=15962004; DOI=10.1038/sj.emboj.7600709;
RA Matsumoto T., Bohman S., Dixelius J., Berge T., Dimberg A.,
RA Magnusson P., Wang L., Wikner C., Qi J.H., Wernstedt C., Wu J.,
RA Bruheim S., Mugishima H., Mukhopadhyay D., Spurkland A.,
RA Claesson-Welsh L.;
RT "VEGF receptor-2 Y951 signaling and a role for the adapter molecule
RT TSAd in tumor angiogenesis.";
RL EMBO J. 24:2342-2353(2005).
RN [25]
RP FUNCTION IN ENDOTHELIAL CELL MIGRATION; ACTIVATION OF MAP KINASES AND
RP IN PHOSPHORYLATION OF FYN; SRC AND NCK1, INTERACTION WITH GRB2; FYN
RP AND NCK1, AND MUTAGENESIS OF TYR-1214.
RX PubMed=16966330; DOI=10.1074/jbc.M603928200;
RA Lamalice L., Houle F., Huot J.;
RT "Phosphorylation of Tyr1214 within VEGFR-2 triggers the recruitment of
RT Nck and activation of Fyn leading to SAPK2/p38 activation and
RT endothelial cell migration in response to VEGF.";
RL J. Biol. Chem. 281:34009-34020(2006).
RN [26]
RP SUBCELLULAR LOCATION, UBIQUITINATION, AND DEGRADATION.
RX PubMed=17004325; DOI=10.1111/j.1600-0854.2006.00462.x;
RA Ewan L.C., Jopling H.M., Jia H., Mittar S., Bagherzadeh A.,
RA Howell G.J., Walker J.H., Zachary I.C., Ponnambalam S.;
RT "Intrinsic tyrosine kinase activity is required for vascular
RT endothelial growth factor receptor 2 ubiquitination, sorting and
RT degradation in endothelial cells.";
RL Traffic 7:1270-1282(2006).
RN [27]
RP FUNCTION IN ACTIVATION OF AKT1; PHOSPHORYLATION OF PLCG1 AND NOS3 AND
RP REGULATION OF NITRIC OXIDE PRODUCTION, PHOSPHORYLATION AT TYR-801, AND
RP MUTAGENESIS OF TYR-801.
RX PubMed=17303569; DOI=10.1074/jbc.M609048200;
RA Blanes M.G., Oubaha M., Rautureau Y., Gratton J.P.;
RT "Phosphorylation of tyrosine 801 of vascular endothelial growth factor
RT receptor-2 is necessary for Akt-dependent endothelial nitric-oxide
RT synthase activation and nitric oxide release from endothelial cells.";
RL J. Biol. Chem. 282:10660-10669(2007).
RN [28]
RP PHOSPHORYLATION AT TYR-951; TYR-1175 AND TYR-1214, AND
RP DEPHOSPHORYLATION BY PTPRB.
RX PubMed=19136612; DOI=10.1096/fj.08-123810;
RA Mellberg S., Dimberg A., Bahram F., Hayashi M., Rennel E., Ameur A.,
RA Westholm J.O., Larsson E., Lindahl P., Cross M.J., Claesson-Welsh L.;
RT "Transcriptional profiling reveals a critical role for tyrosine
RT phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial
RT cell morphogenesis.";
RL FASEB J. 23:1490-1502(2009).
RN [29]
RP PHOSPHORYLATION AT TYR-801; TYR-951; TYR-996; TYR-1054; TYR-1059;
RP TYR-1175 AND TYR-1214; DEPHOSPHORYLATION BY PTPRJ AT TYR-951; TYR-996;
RP TYR-1054; TYR-1059; TYR-1175 AND TYR-1214.
RX PubMed=18936167; DOI=10.1128/MCB.01374-08;
RA Chabot C., Spring K., Gratton J.P., Elchebly M., Royal I.;
RT "New role for the protein tyrosine phosphatase DEP-1 in Akt activation
RT and endothelial cell survival.";
RL Mol. Cell. Biol. 29:241-253(2009).
RN [30]
RP FUNCTION AS VEGFA RECEPTOR IN TUMOR ANGIOGENESIS, SUBCELLULAR
RP LOCATION, AND UBIQUITINATION.
RX PubMed=19834490; DOI=10.1038/cdd.2009.152;
RA Zhang Z., Neiva K.G., Lingen M.W., Ellis L.M., Nor J.E.;
RT "VEGF-dependent tumor angiogenesis requires inverse and reciprocal
RT regulation of VEGFR1 and VEGFR2.";
RL Cell Death Differ. 17:499-512(2010).
RN [31]
RP FUNCTION IN LYMPHANGIOGENESIS (ISOFORM 2).
RX PubMed=20179233; DOI=10.1158/1078-0432.CCR-09-1936;
RA Becker J., Pavlakovic H., Ludewig F., Wilting F., Weich H.A.,
RA Albuquerque R., Ambati J., Wilting J.;
RT "Neuroblastoma progression correlates with downregulation of the
RT lymphangiogenesis inhibitor sVEGFR-2.";
RL Clin. Cancer Res. 16:1431-1441(2010).
RN [32]
RP INTERACTION WITH VEGFC AND FLT4, SUBCELLULAR LOCATION, AND FUNCTION IN
RP ANGIOGENESIS.
RX PubMed=20224550; DOI=10.1038/emboj.2010.30;
RA Nilsson I., Bahram F., Li X., Gualandi L., Koch S., Jarvius M.,
RA Soderberg O., Anisimov A., Kholova I., Pytowski B., Baldwin M.,
RA Yla-Herttuala S., Alitalo K., Kreuger J., Claesson-Welsh L.;
RT "VEGF receptor 2/-3 heterodimers detected in situ by proximity
RT ligation on angiogenic sprouts.";
RL EMBO J. 29:1377-1388(2010).
RN [33]
RP SUBCELLULAR LOCATION.
RX PubMed=21539813; DOI=10.1016/j.bbrc.2011.04.093;
RA Jopling H.M., Howell G.J., Gamper N., Ponnambalam S.;
RT "The VEGFR2 receptor tyrosine kinase undergoes constitutive endosome-
RT to-plasma membrane recycling.";
RL Biochem. Biophys. Res. Commun. 410:170-176(2011).
RN [34]
RP FUNCTION IN LYMPHANGIOGENESIS, AND INTERACTION WITH FLT4 AND VEGFC.
RX PubMed=20705758; DOI=10.1182/blood-2010-02-267427;
RA Nakao S., Zandi S., Hata Y., Kawahara S., Arita R., Schering A.,
RA Sun D., Melhorn M.I., Ito Y., Lara-Castillo N., Ishibashi T.,
RA Hafezi-Moghadam A.;
RT "Blood vessel endothelial VEGFR-2 delays lymphangiogenesis: an
RT endogenous trapping mechanism links lymph- and angiogenesis.";
RL Blood 117:1081-1090(2011).
RN [35]
RP REVIEW ON ROLE IN ANGIOGENESIS.
RX PubMed=17002866;
RA Shibuya M.;
RT "Differential roles of vascular endothelial growth factor receptor-1
RT and receptor-2 in angiogenesis.";
RL J. Biochem. Mol. Biol. 39:469-478(2006).
RN [36]
RP REVIEW.
RX PubMed=17658244; DOI=10.1016/j.cellsig.2007.05.013;
RA Holmes K., Roberts O.L., Thomas A.M., Cross M.J.;
RT "Vascular endothelial growth factor receptor-2: structure, function,
RT intracellular signalling and therapeutic inhibition.";
RL Cell. Signal. 19:2003-2012(2007).
RN [37]
RP REVIEW ON STRUCTURE AND FUNCTION.
RX PubMed=18680722; DOI=10.1016/j.bbrc.2008.07.121;
RA Roskoski R. Jr.;
RT "VEGF receptor protein-tyrosine kinases: structure and regulation.";
RL Biochem. Biophys. Res. Commun. 375:287-291(2008).
RN [38]
RP REVIEW ON ROLE IN ANGIOGENESIS AND CANCER.
RX PubMed=19230644; DOI=10.1016/j.ceb.2008.12.012;
RA Lohela M., Bry M., Tammela T., Alitalo K.;
RT "VEGFs and receptors involved in angiogenesis versus
RT lymphangiogenesis.";
RL Curr. Opin. Cell Biol. 21:154-165(2009).
RN [39]
RP REVIEW ON LIGAND SPECIFICITY; FUNCTION; STRUCTURE; PHOSPHORYLATION AND
RP SIGNALING.
RX PubMed=19761875; DOI=10.1016/j.bbapap.2009.09.002;
RA Grunewald F.S., Prota A.E., Giese A., Ballmer-Hofer K.;
RT "Structure-function analysis of VEGF receptor activation and the role
RT of coreceptors in angiogenic signaling.";
RL Biochim. Biophys. Acta 1804:567-580(2010).
RN [40]
RP REVIEW ON ROLE IN ANGIOGENESIS AND CANCER.
RX PubMed=20462514; DOI=10.1016/j.bbcan.2010.04.004;
RA Guo S., Colbert L.S., Fuller M., Zhang Y., Gonzalez-Perez R.R.;
RT "Vascular endothelial growth factor receptor-2 in breast cancer.";
RL Biochim. Biophys. Acta 1806:108-121(2010).
RN [41]
RP REVIEW ON ROLE IN ANGIOGENESIS AND CANCER.
RX PubMed=21779435; DOI=10.1177/1947601910392987;
RA Shibuya M.;
RT "Tyrosine kinase receptor Flt/VEGFR family: its characterization
RT related to angiogenesis and cancer.";
RL Genes Cancer 1:1119-1123(2010).
RN [42]
RP REVIEW ON LIGAND SPECIFICITY; FUNCTION; STRUCTURE; PHOSPHORYLATION AND
RP SIGNALING.
RX PubMed=21711246; DOI=10.1042/BJ20110301;
RA Koch S., Tugues S., Li X., Gualandi L., Claesson-Welsh L.;
RT "Signal transduction by vascular endothelial growth factor
RT receptors.";
RL Biochem. J. 437:169-183(2011).
RN [43]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-982 AND SER-984, AND
RP MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 806-1171, FUNCTION,
RP PHOSPHORYLATION AT TYR-1059, AND MASS SPECTROMETRY.
RX PubMed=10368301; DOI=10.1016/S0969-2126(99)80042-2;
RA McTigue M.A., Wickersham J.A., Pinko C., Showalter R.E., Parast C.V.,
RA Tempczyk-Russell A., Gehring M.R., Mroczkowski B., Kan C.-C.,
RA Villafranca J.E., Appelt K.;
RT "Crystal structure of the kinase domain of human vascular endothelial
RT growth factor receptor 2: a key enzyme in angiogenesis.";
RL Structure 7:319-330(1999).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (1.71 ANGSTROMS) OF 806-1171 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR.
RX PubMed=15837294; DOI=10.1016/j.bmcl.2005.03.034;
RA Miyazaki Y., Matsunaga S., Tang J., Maeda Y., Nakano M.,
RA Philippe R.J., Shibahara M., Liu W., Sato H., Wang L., Nolte R.T.;
RT "Novel 4-amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual
RT inhibitors.";
RL Bioorg. Med. Chem. Lett. 15:2203-2207(2005).
RN [46]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 815-1171 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR.
RX PubMed=17253678; DOI=10.1021/jm061107l;
RA Hodous B.L., Geuns-Meyer S.D., Hughes P.E., Albrecht B.K., Bellon S.,
RA Bready J., Caenepeel S., Cee V.J., Chaffee S.C., Coxon A., Emery M.,
RA Fretland J., Gallant P., Gu Y., Hoffman D., Johnson R.E., Kendall R.,
RA Kim J.L., Long A.M., Morrison M., Olivieri P.R., Patel V.F.,
RA Polverino A., Rose P., Tempest P., Wang L., Whittington D.A., Zhao H.;
RT "Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-
RT triazine Tie-2 kinase inhibitor.";
RL J. Med. Chem. 50:611-626(2007).
RN [47]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 806-1171 IN COMPLEX WITH
RP SYNTHETIC INHIBITOR, AND FUNCTION.
RX PubMed=18529047; DOI=10.1021/jm8001185;
RA Peifer C., Selig R., Kinkel K., Ott D., Totzke F., Schaechtele C.,
RA Heidenreich R., Roecken M., Schollmeyer D., Laufer S.;
RT "Design, synthesis, and biological evaluation of novel 3-aryl-4-(1H-
RT indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as vascular endothelial
RT growth factor receptor (VEGF-R) inhibitors.";
RL J. Med. Chem. 51:3814-3824(2008).
RN [48]
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 657-764, SUBUNIT,
RP AUTOPHOSPHORYLATION, FUNCTION IN VEGFA SIGNALING AND ACTIVATION OF
RP MAPK1/ERK2 AND MAPK3/ERK1, AND MUTAGENESIS OF ARG-726 AND ASP-731.
RX PubMed=20080685; DOI=10.1073/pnas.0914052107;
RA Yang Y., Xie P., Opatowsky Y., Schlessinger J.;
RT "Direct contacts between extracellular membrane-proximal domains are
RT required for VEGF receptor activation and cell signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:1906-1911(2010).
RN [49]
RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 120-326 IN COMPLEX WITH
RP VEGFC, INTERACTION WITH VEGFC, DOMAIN, DISULFIDE BONDS, AND
RP GLYCOSYLATION AT ASN-143; ASN-245 AND ASN-318.
RX PubMed=20145116; DOI=10.1073/pnas.0914318107;
RA Leppanen V.M., Prota A.E., Jeltsch M., Anisimov A., Kalkkinen N.,
RA Strandin T., Lankinen H., Goldman A., Ballmer-Hofer K., Alitalo K.;
RT "Structural determinants of growth factor binding and specificity by
RT VEGF receptor 2.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:2425-2430(2010).
RN [50]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 220-338 IN COMPLEX WITH
RP ANTIBODY FRAGMENT, DISULFIDE BOND, AND GLYCOSYLATION AT ASN-245 AND
RP ASN-318.
RX PubMed=21827946; DOI=10.1016/j.str.2011.01.019;
RA Franklin M.C., Navarro E.C., Wang Y., Patel S., Singh P., Zhang Y.,
RA Persaud K., Bari A., Griffith H., Shen L., Balderes P., Kussie P.;
RT "The structural basis for the function of two anti-VEGF receptor 2
RT antibodies.";
RL Structure 19:1097-1107(2011).
RN [51]
RP VARIANT HCI SER-1147.
RX PubMed=11807987; DOI=10.1002/gcc.10028;
RA Walter J.W., North P.E., Waner M., Mizeracki A., Blei F.,
RA Walker J.W.T., Reinisch J.F., Marchuk D.A.;
RT "Somatic mutation of vascular endothelial growth factor receptors in
RT juvenile hemangioma.";
RL Genes Chromosomes Cancer 33:295-303(2002).
RN [52]
RP VARIANTS [LARGE SCALE ANALYSIS] LEU-275 AND ARG-873.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [53]
RP VARIANTS [LARGE SCALE ANALYSIS] ARG-2; MET-136; GLY-248; ILE-297;
RP VAL-462; HIS-472; ARG-482; ARG-539; MET-689; ASN-814 AND THR-1065.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [54]
RP VARIANT HCI SUSCEPTIBILITY ARG-482.
RX PubMed=18931684; DOI=10.1038/nm.1877;
RA Jinnin M., Medici D., Park L., Limaye N., Liu Y., Boscolo E.,
RA Bischoff J., Vikkula M., Boye E., Olsen B.R.;
RT "Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2
RT signaling in infantile hemangioma.";
RL Nat. Med. 14:1236-1246(2008).
CC -!- FUNCTION: Tyrosine-protein kinase that acts as a cell-surface
CC receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in
CC the regulation of angiogenesis, vascular development, vascular
CC permeability, and embryonic hematopoiesis. Promotes proliferation,
CC survival, migration and differentiation of endothelial cells.
CC Promotes reorganization of the actin cytoskeleton. Isoforms
CC lacking a transmembrane domain, such as isoform 2 and isoform 3,
CC may function as decoy receptors for VEGFA, VEGFC and/or VEGFD.
CC Isoform 2 plays an important role as negative regulator of VEGFA-
CC and VEGFC-mediated lymphangiogenesis by limiting the amount of
CC free VEGFA and/or VEGFC and preventing their binding to FLT4.
CC Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding
CC of vascular growth factors to isoform 1 leads to the activation of
CC several signaling cascades. Activation of PLCG1 leads to the
CC production of the cellular signaling molecules diacylglycerol and
CC inositol 1,4,5-trisphosphate and the activation of protein kinase
CC C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP
CC kinase signaling pathway, as well as of the AKT1 signaling
CC pathway. Mediates phosphorylation of PIK3R1, the regulatory
CC subunit of phosphatidylinositol 3-kinase, reorganization of the
CC actin cytoskeleton and activation of PTK2/FAK1. Required for
CC VEGFA-mediated induction of NOS2 and NOS3, leading to the
CC production of the signaling molecule nitric oxide (NO) by
CC endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation
CC of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.
CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
CC -!- ENZYME REGULATION: Present in an inactive conformation in the
CC absence of bound ligand. Binding of VEGFA, VEGFC or VEGFD leads to
CC dimerization and activation by autophosphorylation on tyrosine
CC residues. Inhibited by the small molecule PTK inhibitor SU5614
CC ((3Z)-5-Chloro-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-1,3-
CC dihydro-2H-indol-2-one).
CC -!- SUBUNIT: Interacts with MYOF (By similarity). Interacts with
CC VEGFA, VEGFC and VEGFD. Monomer in the absence of bound VEGFA,
CC VEGFC or VEGFD. Homodimer in the presence of bound dimeric VEGFA,
CC VEGFC or VEGFD. Can also form heterodimers with FLT1 and FLT4.
CC Interacts (tyrosine phosphorylated) with FYN, NCK1, PLCG1 and SHB.
CC Interacts with HIV-1 Tat. Interacts with CBL. Interacts with
CC SH2D2A/TSAD and GRB2.
CC -!- INTERACTION:
CC P35916:FLT4; NbExp=3; IntAct=EBI-1005487, EBI-1005467;
CC P08581:MET; NbExp=3; IntAct=EBI-1005487, EBI-1039152;
CC P12931:SRC; NbExp=2; IntAct=EBI-1005487, EBI-621482;
CC P15692-4:VEGFA; NbExp=2; IntAct=EBI-1005487, EBI-1026691;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I
CC membrane protein. Cytoplasm. Nucleus. Cytoplasmic vesicle. Early
CC endosome. Note=Detected on caveolae-enriched lipid rafts at the
CC cell surface. Is recycled from the plasma membrane to endosomes
CC and back again. Phosphorylation triggered by VEGFA binding
CC promotes internalization and subsequent degradation. VEGFA binding
CC triggers internalization and translocation to the nucleus.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Secreted (Probable).
CC -!- SUBCELLULAR LOCATION: Isoform 3: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=mbVegfr-2;
CC IsoId=P35968-1; Sequence=Displayed;
CC Name=2; Synonyms=sVegfr-2;
CC IsoId=P35968-2; Sequence=VSP_041988, VSP_041989;
CC Name=3; Synonyms=VEGFR2-712;
CC IsoId=P35968-3; Sequence=VSP_041990, VSP_041991;
CC -!- TISSUE SPECIFICITY: Detected in cornea (at protein level). Widely
CC expressed.
CC -!- DOMAIN: The second and third Ig-like C2-type (immunoglobulin-like)
CC domains are sufficient for VEGFC binding.
CC -!- PTM: N-glycosylated.
CC -!- PTM: Ubiquitinated. Tyrosine phosphorylation of the receptor
CC promotes its poly-ubiquitination, leading to its degradation via
CC the proteasome or lysosomal proteases.
CC -!- PTM: Autophosphorylated on tyrosine residues upon ligand binding.
CC Autophosphorylation occurs in trans, i.e. one subunit of the
CC dimeric receptor phosphorylates tyrosine residues on the other
CC subunit. Phosphorylation at Tyr-951 is important for interaction
CC with SH2D2A/TSAD and VEGFA-mediated reorganization of the actin
CC cytoskeleton. Phosphorylation at Tyr-1175 is important for
CC interaction with PLCG1 and SHB. Phosphorylation at Tyr-1214 is
CC important for interaction with NCK1 and FYN. Dephosphorylated by
CC PTPRB. Dephosphorylated by PTPRJ at Tyr-951, Tyr-996, Tyr-1054,
CC Tyr-1059, Tyr-1175 and Tyr-1214.
CC -!- DISEASE: Hemangioma, capillary infantile (HCI) [MIM:602089]: A
CC condition characterized by dull red, firm, dome-shaped
CC hemangiomas, sharply demarcated from surrounding skin, usually
CC presenting at birth or occurring within the first two or three
CC months of life. They result from highly proliferative, localized
CC growth of capillary endothelium and generally undergo regression
CC and involution without scarring. Note=Disease susceptibility is
CC associated with variations affecting the gene represented in this
CC entry.
CC -!- DISEASE: Note=Plays a major role in tumor angiogenesis. In case of
CC HIV-1 infection, the interaction with extracellular viral Tat
CC protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. CSF-1/PDGF receptor subfamily.
CC -!- SIMILARITY: Contains 7 Ig-like C2-type (immunoglobulin-like)
CC domains.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -----------------------------------------------------------------------
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DR EMBL; EU826563; ACF47599.1; -; mRNA.
DR EMBL; FJ899739; ACR78514.1; -; mRNA.
DR EMBL; AF035121; AAB88005.1; -; mRNA.
DR EMBL; AF063658; AAC16450.1; -; mRNA.
DR EMBL; AC021220; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC111194; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC131822; AAI31823.1; -; mRNA.
DR EMBL; L04947; AAA59459.1; -; mRNA.
DR EMBL; X61656; CAA43837.1; -; mRNA.
DR EMBL; X89776; CAA61916.1; -; Genomic_DNA.
DR IPI; IPI00021396; -.
DR PIR; JC1402; JC1402.
DR RefSeq; NP_002244.1; NM_002253.2.
DR UniGene; Hs.479756; -.
DR PDB; 1VR2; X-ray; 2.40 A; A=806-1171.
DR PDB; 1Y6A; X-ray; 2.10 A; A=806-1171.
DR PDB; 1Y6B; X-ray; 2.10 A; A=806-1171.
DR PDB; 1YWN; X-ray; 1.71 A; A=806-1171.
DR PDB; 2OH4; X-ray; 2.05 A; A=806-1171.
DR PDB; 2P2H; X-ray; 1.95 A; A=815-1171.
DR PDB; 2P2I; X-ray; 2.40 A; A/B=815-1171.
DR PDB; 2QU5; X-ray; 2.95 A; A=815-1171.
DR PDB; 2QU6; X-ray; 2.10 A; A/B=815-1171.
DR PDB; 2RL5; X-ray; 2.65 A; A=815-1171.
DR PDB; 2X1W; X-ray; 2.70 A; L/M/N/O=120-326.
DR PDB; 2X1X; X-ray; 3.10 A; R=120-326.
DR PDB; 2XIR; X-ray; 1.50 A; A=806-1171.
DR PDB; 3B8Q; X-ray; 2.75 A; A/B=815-1171.
DR PDB; 3B8R; X-ray; 2.70 A; A/B=815-1171.
DR PDB; 3BE2; X-ray; 1.75 A; A=815-1171.
DR PDB; 3C7Q; X-ray; 2.10 A; A=806-1171.
DR PDB; 3CJF; X-ray; 2.15 A; A=806-1168.
DR PDB; 3CJG; X-ray; 2.25 A; A=806-1168.
DR PDB; 3CP9; X-ray; 2.50 A; A/B=815-1171.
DR PDB; 3CPB; X-ray; 2.70 A; A/B=815-1171.
DR PDB; 3CPC; X-ray; 2.40 A; A/B=815-1171.
DR PDB; 3DTW; X-ray; 2.90 A; A/B=815-1171.
DR PDB; 3EFL; X-ray; 2.20 A; A/B=815-1171.
DR PDB; 3EWH; X-ray; 1.60 A; A=815-1171.
DR PDB; 3KVQ; X-ray; 2.70 A; A=657-764.
DR PDB; 3S35; X-ray; 2.20 A; X=220-338.
DR PDB; 3S36; X-ray; 3.20 A; X=220-338.
DR PDB; 3S37; X-ray; 2.70 A; X=220-338.
DR PDB; 3U6J; X-ray; 2.15 A; A=815-1171.
DR PDB; 3VHE; X-ray; 1.55 A; A=811-1169.
DR PDB; 3VHK; X-ray; 2.49 A; A=806-1171.
DR PDB; 3VID; X-ray; 2.30 A; A=813-1168.
DR PDB; 3VNT; X-ray; 1.64 A; A=806-1171.
DR PDB; 3VO3; X-ray; 1.52 A; A=806-1171.
DR PDB; 4AG8; X-ray; 1.95 A; A=806-1171.
DR PDB; 4AGC; X-ray; 2.00 A; A=787-1171.
DR PDB; 4AGD; X-ray; 2.81 A; A=787-1171.
DR PDB; 4ASD; X-ray; 2.03 A; A=787-1171.
DR PDB; 4ASE; X-ray; 1.83 A; A=787-1171.
DR PDBsum; 1VR2; -.
DR PDBsum; 1Y6A; -.
DR PDBsum; 1Y6B; -.
DR PDBsum; 1YWN; -.
DR PDBsum; 2OH4; -.
DR PDBsum; 2P2H; -.
DR PDBsum; 2P2I; -.
DR PDBsum; 2QU5; -.
DR PDBsum; 2QU6; -.
DR PDBsum; 2RL5; -.
DR PDBsum; 2X1W; -.
DR PDBsum; 2X1X; -.
DR PDBsum; 2XIR; -.
DR PDBsum; 3B8Q; -.
DR PDBsum; 3B8R; -.
DR PDBsum; 3BE2; -.
DR PDBsum; 3C7Q; -.
DR PDBsum; 3CJF; -.
DR PDBsum; 3CJG; -.
DR PDBsum; 3CP9; -.
DR PDBsum; 3CPB; -.
DR PDBsum; 3CPC; -.
DR PDBsum; 3DTW; -.
DR PDBsum; 3EFL; -.
DR PDBsum; 3EWH; -.
DR PDBsum; 3KVQ; -.
DR PDBsum; 3S35; -.
DR PDBsum; 3S36; -.
DR PDBsum; 3S37; -.
DR PDBsum; 3U6J; -.
DR PDBsum; 3VHE; -.
DR PDBsum; 3VHK; -.
DR PDBsum; 3VID; -.
DR PDBsum; 3VNT; -.
DR PDBsum; 3VO3; -.
DR PDBsum; 4AG8; -.
DR PDBsum; 4AGC; -.
DR PDBsum; 4AGD; -.
DR PDBsum; 4ASD; -.
DR PDBsum; 4ASE; -.
DR ProteinModelPortal; P35968; -.
DR DIP; DIP-486N; -.
DR IntAct; P35968; 7.
DR MINT; MINT-127732; -.
DR STRING; 9606.ENSP00000263923; -.
DR PhosphoSite; P35968; -.
DR DMDM; 9087218; -.
DR PaxDb; P35968; -.
DR PRIDE; P35968; -.
DR DNASU; 3791; -.
DR Ensembl; ENST00000263923; ENSP00000263923; ENSG00000128052.
DR GeneID; 3791; -.
DR KEGG; hsa:3791; -.
DR UCSC; uc003has.3; human.
DR CTD; 3791; -.
DR GeneCards; GC04M055944; -.
DR HGNC; HGNC:6307; KDR.
DR HPA; CAB004028; -.
DR MIM; 191306; gene.
DR MIM; 602089; phenotype.
DR neXtProt; NX_P35968; -.
DR Orphanet; 91415; Familial capillary hemangioma.
DR PharmGKB; PA30086; -.
DR eggNOG; COG0515; -.
DR HOVERGEN; HBG053432; -.
DR InParanoid; P35968; -.
DR KO; K05098; -.
DR OMA; QDYRSPF; -.
DR OrthoDB; EOG48KR9F; -.
DR PhylomeDB; P35968; -.
DR BRENDA; 2.7.10.1; 2681.
DR Pathway_Interaction_DB; avb3_integrin_pathway; Integrins in angiogenesis.
DR Pathway_Interaction_DB; s1p_s1p1_pathway; S1P1 pathway.
DR Pathway_Interaction_DB; vegfr1_2_pathway; Signaling events mediated by VEGFR1 and VEGFR2.
DR Reactome; REACT_111102; Signal Transduction.
DR BindingDB; P35968; -.
DR ChEMBL; CHEMBL279; -.
DR DrugBank; DB00398; Sorafenib.
DR DrugBank; DB01268; Sunitinib.
DR EvolutionaryTrace; P35968; -.
DR GenomeRNAi; 3791; -.
DR NextBio; 14887; -.
DR ArrayExpress; P35968; -.
DR Bgee; P35968; -.
DR CleanEx; HS_KDR; -.
DR Genevestigator; P35968; -.
DR GermOnline; ENSG00000128052; Homo sapiens.
DR GO; GO:0016023; C:cytoplasmic membrane-bounded vesicle; IEA:UniProtKB-SubCell.
DR GO; GO:0005769; C:early endosome; ISS:BHF-UCL.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Compara.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; IDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0051879; F:Hsp90 protein binding; TAS:BHF-UCL.
DR GO; GO:0004716; F:receptor signaling protein tyrosine kinase activity; TAS:BHF-UCL.
DR GO; GO:0005021; F:vascular endothelial growth factor-activated receptor activity; IDA:UniProtKB.
DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; IEA:Compara.
DR GO; GO:0055074; P:calcium ion homeostasis; IEA:Compara.
DR GO; GO:0035584; P:calcium-mediated signaling using intracellular calcium source; IMP:UniProtKB.
DR GO; GO:0045165; P:cell fate commitment; IEA:Compara.
DR GO; GO:0048469; P:cell maturation; IEA:Compara.
DR GO; GO:0002042; P:cell migration involved in sprouting angiogenesis; ISS:BHF-UCL.
DR GO; GO:0035162; P:embryonic hemopoiesis; ISS:UniProtKB.
DR GO; GO:0045446; P:endothelial cell differentiation; IEA:Compara.
DR GO; GO:0003158; P:endothelium development; ISS:UniProtKB.
DR GO; GO:0048286; P:lung alveolus development; IEA:Compara.
DR GO; GO:0001945; P:lymph vessel development; IEA:Compara.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IDA:UniProtKB.
DR GO; GO:0001541; P:ovarian follicle development; IEA:Compara.
DR GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; ISS:BHF-UCL.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:UniProtKB.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; IMP:BHF-UCL.
DR GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IMP:UniProtKB.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; IDA:BHF-UCL.
DR GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; IEA:Compara.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; IDA:UniProtKB.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase cascade; IDA:UniProtKB.
DR GO; GO:0050927; P:positive regulation of positive chemotaxis; IDA:BHF-UCL.
DR GO; GO:0008360; P:regulation of cell shape; IDA:BHF-UCL.
DR GO; GO:0043129; P:surfactant homeostasis; IEA:Compara.
DR GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0001570; P:vasculogenesis; ISS:UniProtKB.
DR GO; GO:0019048; P:virus-host interaction; IEA:UniProtKB-KW.
DR Gene3D; 2.60.40.10; -; 8.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR013106; Ig_V-set.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_cat_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR001824; Tyr_kinase_rcpt_3_CS.
DR InterPro; IPR009136; Tyr_kinase_VEGFR2_rcpt.
DR InterPro; IPR009134; Tyr_kinase_VEGFR_rcpt_N.
DR Pfam; PF07679; I-set; 2.
DR Pfam; PF07714; Pkinase_Tyr; 1.
DR Pfam; PF07686; V-set; 1.
DR PRINTS; PR01832; VEGFRECEPTOR.
DR PRINTS; PR01834; VEGFRECEPTR2.
DR SMART; SM00409; IG; 4.
DR SMART; SM00408; IGc2; 2.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF56112; Kinase_like; 1.
DR PROSITE; PS50835; IG_LIKE; 5.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00240; RECEPTOR_TYR_KIN_III; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Angiogenesis; ATP-binding;
KW Cell membrane; Complete proteome; Cytoplasm; Cytoplasmic vesicle;
KW Developmental protein; Differentiation; Disulfide bond; Endosome;
KW Glycoprotein; Host-virus interaction; Immunoglobulin domain; Kinase;
KW Membrane; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Receptor; Reference proteome; Repeat; Secreted; Signal; Transferase;
KW Transmembrane; Transmembrane helix; Tyrosine-protein kinase;
KW Ubl conjugation.
FT SIGNAL 1 19 Potential.
FT CHAIN 20 1356 Vascular endothelial growth factor
FT receptor 2.
FT /FTId=PRO_0000016771.
FT TOPO_DOM 20 764 Extracellular (Potential).
FT TRANSMEM 765 785 Helical; (Potential).
FT TOPO_DOM 786 1356 Cytoplasmic (Potential).
FT DOMAIN 46 110 Ig-like C2-type 1.
FT DOMAIN 141 207 Ig-like C2-type 2.
FT DOMAIN 224 320 Ig-like C2-type 3.
FT DOMAIN 328 414 Ig-like C2-type 4.
FT DOMAIN 421 548 Ig-like C2-type 5.
FT DOMAIN 551 660 Ig-like C2-type 6.
FT DOMAIN 667 753 Ig-like C2-type 7.
FT DOMAIN 834 1162 Protein kinase.
FT NP_BIND 840 848 ATP (Probable).
FT ACT_SITE 1028 1028 Proton acceptor (By similarity).
FT BINDING 868 868 ATP (Probable).
FT SITE 1175 1175 Interaction with SHB (By similarity).
FT MOD_RES 801 801 Phosphotyrosine.
FT MOD_RES 951 951 Phosphotyrosine; by autocatalysis.
FT MOD_RES 982 982 Phosphoserine.
FT MOD_RES 984 984 Phosphoserine.
FT MOD_RES 996 996 Phosphotyrosine; by autocatalysis.
FT MOD_RES 1054 1054 Phosphotyrosine; by autocatalysis.
FT MOD_RES 1059 1059 Phosphotyrosine; by autocatalysis.
FT MOD_RES 1175 1175 Phosphotyrosine; by autocatalysis.
FT MOD_RES 1214 1214 Phosphotyrosine; by autocatalysis.
FT MOD_RES 1305 1305 Phosphotyrosine; by autocatalysis.
FT MOD_RES 1309 1309 Phosphotyrosine; by autocatalysis.
FT MOD_RES 1319 1319 Phosphotyrosine; by autocatalysis.
FT CARBOHYD 46 46 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 66 66 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 96 96 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 143 143 N-linked (GlcNAc...).
FT CARBOHYD 158 158 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 245 245 N-linked (GlcNAc...).
FT CARBOHYD 318 318 N-linked (GlcNAc...).
FT CARBOHYD 374 374 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 395 395 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 511 511 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 523 523 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 580 580 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 613 613 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 619 619 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 631 631 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 675 675 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 704 704 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 721 721 N-linked (GlcNAc...) (Potential).
FT DISULFID 53 103 By similarity.
FT DISULFID 150 200
FT DISULFID 246 307
FT DISULFID 445 530 By similarity.
FT DISULFID 571 642 By similarity.
FT DISULFID 688 737 By similarity.
FT VAR_SEQ 663 678 ERVAPTITGNLENQTT -> GRETILDHCAEAVGMP (in
FT isoform 2).
FT /FTId=VSP_041988.
FT VAR_SEQ 679 1356 Missing (in isoform 2).
FT /FTId=VSP_041989.
FT VAR_SEQ 712 712 G -> E (in isoform 3).
FT /FTId=VSP_041990.
FT VAR_SEQ 713 1356 Missing (in isoform 3).
FT /FTId=VSP_041991.
FT VARIANT 2 2 Q -> R (in a lung adenocarcinoma sample;
FT somatic mutation).
FT /FTId=VAR_042053.
FT VARIANT 136 136 V -> M (in dbSNP:rs35636987).
FT /FTId=VAR_042054.
FT VARIANT 248 248 A -> G (in a renal clear cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_042055.
FT VARIANT 275 275 R -> L (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036126.
FT VARIANT 297 297 V -> I (in dbSNP:rs2305948).
FT /FTId=VAR_022071.
FT VARIANT 462 462 L -> V (in dbSNP:rs56286620).
FT /FTId=VAR_042056.
FT VARIANT 472 472 Q -> H (in dbSNP:rs1870377).
FT /FTId=VAR_020353.
FT VARIANT 482 482 C -> R (in HCI susceptibility; expression
FT of FLT1 in hemangioma endothelial cells
FT is markedly reduced and KDR activity is
FT increased compared to controls; low FLT1
FT expression in hemangioma cells is caused
FT by reduced activity of a pathway
FT involving ITGB1, ANTXR1, KDR and
FT NFATC2IP; the mutation predicts to result
FT in loss-of-function and disruption of the
FT normal association of these molecules;
FT dbSNP:rs34231037).
FT /FTId=VAR_042057.
FT VARIANT 539 539 G -> R (in dbSNP:rs55716939).
FT /FTId=VAR_042058.
FT VARIANT 689 689 T -> M (in dbSNP:rs34038364).
FT /FTId=VAR_042059.
FT VARIANT 814 814 D -> N (in dbSNP:rs35603373).
FT /FTId=VAR_042060.
FT VARIANT 848 848 V -> E (strongly reduced
FT autophosphorylation and kinase activity;
FT dbSNP:rs1139776).
FT /FTId=VAR_046679.
FT VARIANT 873 873 G -> R (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_036127.
FT VARIANT 952 952 V -> I (in dbSNP:rs13129474).
FT /FTId=VAR_046680.
FT VARIANT 1065 1065 A -> T (in dbSNP:rs56302315).
FT /FTId=VAR_042061.
FT VARIANT 1147 1147 P -> S (in HCI; somatic mutation).
FT /FTId=VAR_063147.
FT MUTAGEN 726 726 R->A: Strongly reduced
FT autophosphorylation and activation of MAP
FT kinases.
FT MUTAGEN 731 731 D->A: Strongly reduced
FT autophosphorylation and activation of MAP
FT kinases.
FT MUTAGEN 801 801 Y->F: Abolishes stimulation of nitric
FT oxide synthesis.
FT MUTAGEN 868 868 K->M: Loss of enzyme activity.
FT MUTAGEN 951 951 Y->F: Abolishes reorganization of the
FT actin cytoskeleton and cell migration in
FT response to VEGFA.
FT MUTAGEN 996 996 Y->F: Strongly reduced
FT autophosphorylation. Reduces
FT phosphorylation of PLCG1.
FT MUTAGEN 1054 1054 Y->F: Strongly reduced
FT autophosphorylation. Abolishes
FT phosphorylation of downstream signaling
FT proteins; when associated with F-1059.
FT MUTAGEN 1059 1059 Y->F: Strongly reduced
FT autophosphorylation. Abolishes
FT phosphorylation of downstream signaling
FT proteins; when associated with F-1054.
FT MUTAGEN 1175 1175 Y->F: Abolishes phosphorylation of PLCG1
FT and MAP kinases in response to VEGFA.
FT MUTAGEN 1214 1214 Y->F: Loss of phosphorylation site.
FT Abolishes reorganization of the actin
FT cytoskeleton in response to VEGFA.
FT CONFLICT 2 2 Q -> E (in Ref. 4; AAC16450).
FT CONFLICT 772 772 A -> T (in Ref. 7; AAA59459/CAA43837).
FT CONFLICT 787 787 R -> G (in Ref. 7; AAA59459/CAA43837).
FT CONFLICT 835 835 K -> N (in Ref. 7; AAA59459/CAA43837).
FT CONFLICT 1347 1347 S -> T (in Ref. 7; AAA59459/CAA43837).
FT STRAND 134 138
FT STRAND 145 148
FT STRAND 152 154
FT STRAND 159 164
FT TURN 165 167
FT STRAND 168 170
FT STRAND 174 176
FT STRAND 178 180
FT TURN 181 183
FT STRAND 184 188
FT HELIX 189 191
FT TURN 192 194
FT STRAND 196 202
FT STRAND 214 218
FT STRAND 223 230
FT STRAND 234 238
FT STRAND 242 250
FT STRAND 257 261
FT HELIX 269 272
FT STRAND 279 282
FT STRAND 285 296
FT HELIX 299 301
FT STRAND 303 310
FT STRAND 315 328
FT STRAND 676 679
FT STRAND 684 687
FT STRAND 697 706
FT STRAND 713 716
FT TURN 717 720
FT STRAND 721 724
FT HELIX 729 731
FT STRAND 733 740
FT STRAND 746 755
FT STRAND 804 806
FT TURN 808 810
FT TURN 813 815
FT HELIX 817 819
FT HELIX 824 827
FT HELIX 831 833
FT STRAND 834 842
FT STRAND 844 858
FT STRAND 862 870
FT HELIX 876 892
FT STRAND 901 905
FT STRAND 907 910
FT STRAND 913 917
FT HELIX 924 929
FT TURN 930 933
FT STRAND 934 936
FT TURN 995 998
FT HELIX 1002 1021
FT STRAND 1024 1026
FT HELIX 1031 1033
FT STRAND 1034 1036
FT HELIX 1038 1040
FT STRAND 1042 1044
FT HELIX 1048 1050
FT TURN 1053 1055
FT STRAND 1059 1062
FT STRAND 1065 1067
FT HELIX 1069 1071
FT HELIX 1074 1079
FT HELIX 1084 1099
FT STRAND 1105 1108
FT HELIX 1113 1121
FT HELIX 1133 1142
FT HELIX 1147 1149
FT HELIX 1153 1167
SQ SEQUENCE 1356 AA; 151527 MW; 59E7C44B05CFEBB3 CRC64;
MQSKVLLAVA LWLCVETRAA SVGLPSVSLD LPRLSIQKDI LTIKANTTLQ ITCRGQRDLD
WLWPNNQSGS EQRVEVTECS DGLFCKTLTI PKVIGNDTGA YKCFYRETDL ASVIYVYVQD
YRSPFIASVS DQHGVVYITE NKNKTVVIPC LGSISNLNVS LCARYPEKRF VPDGNRISWD
SKKGFTIPSY MISYAGMVFC EAKINDESYQ SIMYIVVVVG YRIYDVVLSP SHGIELSVGE
KLVLNCTART ELNVGIDFNW EYPSSKHQHK KLVNRDLKTQ SGSEMKKFLS TLTIDGVTRS
DQGLYTCAAS SGLMTKKNST FVRVHEKPFV AFGSGMESLV EATVGERVRI PAKYLGYPPP
EIKWYKNGIP LESNHTIKAG HVLTIMEVSE RDTGNYTVIL TNPISKEKQS HVVSLVVYVP
PQIGEKSLIS PVDSYQYGTT QTLTCTVYAI PPPHHIHWYW QLEEECANEP SQAVSVTNPY
PCEEWRSVED FQGGNKIEVN KNQFALIEGK NKTVSTLVIQ AANVSALYKC EAVNKVGRGE
RVISFHVTRG PEITLQPDMQ PTEQESVSLW CTADRSTFEN LTWYKLGPQP LPIHVGELPT
PVCKNLDTLW KLNATMFSNS TNDILIMELK NASLQDQGDY VCLAQDRKTK KRHCVVRQLT
VLERVAPTIT GNLENQTTSI GESIEVSCTA SGNPPPQIMW FKDNETLVED SGIVLKDGNR
NLTIRRVRKE DEGLYTCQAC SVLGCAKVEA FFIIEGAQEK TNLEIIILVG TAVIAMFFWL
LLVIILRTVK RANGGELKTG YLSIVMDPDE LPLDEHCERL PYDASKWEFP RDRLKLGKPL
GRGAFGQVIE ADAFGIDKTA TCRTVAVKML KEGATHSEHR ALMSELKILI HIGHHLNVVN
LLGACTKPGG PLMVIVEFCK FGNLSTYLRS KRNEFVPYKT KGARFRQGKD YVGAIPVDLK
RRLDSITSSQ SSASSGFVEE KSLSDVEEEE APEDLYKDFL TLEHLICYSF QVAKGMEFLA
SRKCIHRDLA ARNILLSEKN VVKICDFGLA RDIYKDPDYV RKGDARLPLK WMAPETIFDR
VYTIQSDVWS FGVLLWEIFS LGASPYPGVK IDEEFCRRLK EGTRMRAPDY TTPEMYQTML
DCWHGEPSQR PTFSELVEHL GNLLQANAQQ DGKDYIVLPI SETLSMEEDS GLSLPTSPVS
CMEEEEVCDP KFHYDNTAGI SQYLQNSKRK SRPVSVKTFE DIPLEEPEVK VIPDDNQTDS
GMVLASEELK TLEDRTKLSP SFGGMVPSKS RESVASEGSN QTSGYQSGYH SDDTDTTVYS
SEEAELLKLI EIGVQTGSTA QILQPDSGTT LSSPPV
//
