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 16-NOV-2011, entry version 137. 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 MEDLINE=92019839; 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 MEDLINE=96032749; 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 MEDLINE=93038639; 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; 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; 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/FAK, 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 ACTIVIATION 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; 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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-1054 AND TYR-1059, AND RP MASS SPECTROMETRY. RC TISSUE=Lung carcinoma; RX PubMed=18083107; DOI=10.1016/j.cell.2007.11.025; RA Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., RA Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., RA Mitchell J., Wetzel R., Macneill J., Ren J.M., Yuan J., RA Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., RA Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J.; RT "Global survey of phosphotyrosine signaling identifies oncogenic RT kinases in lung cancer."; RL Cell 131:1190-1203(2007). RN [28] 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 [29] 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 [30] 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 [31] RP FUNCTION AS VEGFA RECEPTOR IN 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 [32] 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 [33] 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 [34] 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 [35] 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 [36] 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 [37] 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 [38] 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 [39] 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 [40] 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 [41] 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 [42] 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 [43] 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 [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 haematopoiesis. Promotes CC proliferation, survival, migration and differentiation of CC endothelial cells. Promotes reorganization of the actin CC cytoskeleton. Isoforms lacking a transmembrane domain, such as CC isoform 2 and isoform 3, may function as decoy receptors for CC VEGFA, VEGFC and/or VEGFD. Isoform 2 plays an important role as CC negative regulator of VEGFA- and VEGFC-mediated lymphangiogenesis CC by limiting the amount of free VEGFA and/or VEGFC and preventing CC their binding to FLT4. Modulates FLT1 and FLT4 signaling by CC forming heterodimers. Binding of vascular growth factors to CC isoform 1 leads to the activation of several signaling cascades. CC Activation of PLCG1 leads to the production of the cellular CC signaling molecules diacylglycerol and inositol-1,4,5- CC trisphosphate and the activation of protein kinase C. Mediates CC activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling CC pathway, as well as of the AKT1 signaling pathway. Mediates CC phosphorylation of PIK3R1, the regulatory subunit of CC phosphatidylinositol 3-kinase, reorganization of the actin CC cytoskeleton and activation of PTK2/FAK1. Required for VEGFA- CC mediated induction of NOS2 and NOS3, leading to the production of CC the signaling molecule nitric oxide (NO) by endothelial cells. CC Phosphorylates PLCG1. Promotes phosphorylation of FYN, NCK1, NOS3, CC PIK3R1, PTK2/FAK 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 P12931:SRC; NbExp=2; IntAct=EBI-1005487, EBI-621482; 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: Defects in KDR are associated with susceptibility to CC hemangioma capillary infantile (HCI) [MIM:602089]. HCI are benign, CC highly proliferative lesions involving aberrant localized growth CC of capillary endothelium. They are the most common tumor of CC infancy, occurring in up to 10% of all births. Hemangiomas tend to CC appear shortly after birth and show rapid neonatal growth for up CC to 12 months characterized by endothelial hypercellularity and CC increased numbers of mast cells. This phase is followed by slow CC involution at a rate of about 10% per year and replacement by CC fibrofatty stroma. 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 --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 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 ProteinModelPortal; P35968; -. DR SMR; P35968; 35-119, 122-463, 521-550, 560-756, 815-1171. DR DIP; DIP-486N; -. DR DIP; DIP-5741N; -. DR IntAct; P35968; 5. DR MINT; MINT-127732; -. DR STRING; P35968; -. DR PhosphoSite; P35968; -. DR PRIDE; P35968; -. DR Ensembl; ENST00000263923; ENSP00000263923; ENSG00000128052. DR GeneID; 3791; -. DR KEGG; hsa:3791; -. DR UCSC; uc003has.1; human. DR CTD; 3791; -. DR GeneCards; GC04M051893; -. DR H-InvDB; HIX0031357; -. 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 HOVERGEN; HBG053432; -. DR InParanoid; P35968; -. 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 DrugBank; DB00398; Sorafenib. DR DrugBank; DB01268; Sunitinib. DR NextBio; 14887; -. DR ArrayExpress; P35968; -. DR Bgee; P35968; -. DR CleanEx; HS_KDR; -. DR Genevestigator; P35968; -. DR GermOnline; ENSG00000128052; Homo sapiens. DR GO; GO:0005887; C:integral to plasma membrane; IDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0019838; F:growth factor binding; IPI:BHF-UCL. DR GO; GO:0051879; F:Hsp90 protein binding; TAS:BHF-UCL. DR GO; GO:0005178; F:integrin binding; IPI: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:0001525; P:angiogenesis; TAS:BHF-UCL. DR GO; GO:0035584; P:calcium-mediated signaling using intracellular calcium source; IMP:UniProtKB. DR GO; GO:0035162; P:embryonic hemopoiesis; ISS:UniProtKB. DR GO; GO:0044419; P:interspecies interaction between organisms; IEA:UniProtKB-KW. DR GO; GO:2000352; P:negative regulation of endothelial cell apoptosis; IDA:UniProtKB. DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB. 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: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:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0008360; P:regulation of cell shape; IDA:BHF-UCL. DR GO; GO:0001570; P:vasculogenesis; ISS:UniProtKB. DR InterPro; IPR007110; Ig-like. 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. 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 Gene3D; G3DSA:2.60.40.10; Ig-like_fold; 8. DR KO; K05098; -. 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 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 HELIX 824 827 FT HELIX 831 833 FT STRAND 834 841 FT STRAND 844 855 FT STRAND 858 860 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 HELIX 1002 1021 FT HELIX 1031 1033 FT STRAND 1034 1036 FT STRAND 1042 1044 FT HELIX 1068 1071 FT HELIX 1074 1077 FT HELIX 1084 1099 FT HELIX 1115 1120 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 //