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Vascular endothelial growth factor receptor 2 (VEGFR-2) (EC 2.7.10.1) (Fetal liver kinase 1) (FLK-1) (Kinase insert domain receptor) (KDR) (Protein-tyrosine kinase receptor flk-1) (CD antigen CD309)

 VGFR2_HUMAN             Reviewed;        1356 AA.
P35968; A2RRS0; B5A925; C5IFA0; O60723; Q14178;
01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
01-DEC-2000, sequence version 2.
05-JUL-2017, entry version 200.
RecName: Full=Vascular endothelial growth factor receptor 2;
Short=VEGFR-2;
EC=2.7.10.1;
AltName: Full=Fetal liver kinase 1;
Short=FLK-1;
AltName: Full=Kinase insert domain receptor;
Short=KDR;
AltName: Full=Protein-tyrosine kinase receptor flk-1;
AltName: CD_antigen=CD309;
Flags: Precursor;
Name=KDR; Synonyms=FLK1, VEGFR2;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), INTERACTION WITH VEGFC, AND
SUBCELLULAR LOCATION.
PubMed=18593464; DOI=10.1186/ar2447;
Jin P., Zhang J., Sumariwalla P.F., Ni I., Jorgensen B., Crawford D.,
Phillips S., Feldmann M., Shepard H.M., Paleolog E.M.;
"Novel splice variants derived from the receptor tyrosine kinase
superfamily are potential therapeutics for rheumatoid arthritis.";
Arthritis Res. Ther. 10:R73-R73(2008).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), FUNCTION IN INHIBITION OF
LYMPHANGIOGENESIS, INTERACTION WITH VEGFC, AND TISSUE SPECIFICITY.
PubMed=19668192; DOI=10.1038/nm.2018;
Albuquerque R.J., Hayashi T., Cho W.G., Kleinman M.E., Dridi S.,
Takeda A., Baffi J.Z., Yamada K., Kaneko H., Green M.G., Chappell J.,
Wilting J., Weich H.A., Yamagami S., Amano S., Mizuki N.,
Alexander J.S., Peterson M.L., Brekken R.A., Hirashima M., Capoor S.,
Usui T., Ambati B.K., Ambati J.;
"Alternatively spliced vascular endothelial growth factor receptor-2
is an essential endogenous inhibitor of lymphatic vessel growth.";
Nat. Med. 15:1023-1030(2009).
[3]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Yin L.Y., Wu Y., Patterson C.;
"Full length human KDR/flk-1 sequence.";
Submitted (DEC-1997) to the EMBL/GenBank/DDBJ databases.
[4]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
TISSUE=Umbilical vein;
Yu Y., Whitney R.G., Sato J.D.;
"Coding region for human VEGF receptor KDR (VEGFR-2).";
Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases.
[5]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15815621; DOI=10.1038/nature03466;
Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
Waterston R.H., Wilson R.K.;
"Generation and annotation of the DNA sequences of human chromosomes 2
and 4.";
Nature 434:724-731(2005).
[6]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
HIS-472.
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[7]
NUCLEOTIDE SEQUENCE [MRNA] OF 3-1356 (ISOFORM 1), AND VARIANT GLU-848.
TISSUE=Umbilical vein;
PubMed=1656371;
Terman B.I., Carrion M.E., Kovacs E., Rasmussen B.A., Eddy R.L.,
Shows T.B.;
"Identification of a new endothelial cell growth factor receptor
tyrosine kinase.";
Oncogene 6:1677-1683(1991).
[8]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-22.
PubMed=7559454; DOI=10.1074/jbc.270.39.23111;
Patterson C., Perrella M.A., Hsieh C.-M., Yoshizumi M., Lee M.-E.,
Harber E.;
"Cloning and functional analysis of the promoter for KDR/flk-1, a
receptor for vascular endothelial growth factor.";
J. Biol. Chem. 270:23111-23118(1995).
[9]
FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH VEGFA.
PubMed=1417831; DOI=10.1016/0006-291X(92)90483-2;
Terman B.I., Dougher-Vermazen M., Carrion M.E., Dimitrov D.,
Armellino D.C., Gospodarowicz D., Boehlen P.;
"Identification of the KDR tyrosine kinase as a receptor for vascular
endothelial cell growth factor.";
Biochem. Biophys. Res. Commun. 187:1579-1586(1992).
[10]
FUNCTION AS VEGFA RECEPTOR; IN REGULATION OF CELL SHAPE; ACTIN
CYTOSKELETON REORGANIZATION; CELL MIGRATION AND CELL PROLIFERATION,
AND AUTOPHOSPHORYLATION.
PubMed=7929439;
Waltenberger J., Claesson-Welsh L., Siegbahn A., Shibuya M.,
Heldin C.H.;
"Different signal transduction properties of KDR and Flt1, two
receptors for vascular endothelial growth factor.";
J. Biol. Chem. 269:26988-26995(1994).
[11]
FUNCTION IN VEGFA SIGNALING; PHOSPHORYLATION OF PLCG1; ACTIVATION OF
MAP KINASES AND IN PROMOTING PROLIFERATION OF ENDOTHELIAL CELLS,
INTERACTION WITH VEGFA AND PLCG1, AUTOPHOSPHORYLATION, SUBCELLULAR
LOCATION, AND GLYCOSYLATION.
PubMed=9160888; DOI=10.1038/sj.onc.1201047;
Takahashi T., Shibuya M.;
"The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the
PLC-gamma pathway and partially induces mitotic signals in NIH3T3
fibroblasts.";
Oncogene 14:2079-2089(1997).
[12]
FUNCTION IN INDUCTION OF NOS2 AND NOS3.
PubMed=9837777; DOI=10.1006/bbrc.1998.9719;
Kroll J., Waltenberger J.;
"VEGF-A induces expression of eNOS and iNOS in endothelial cells via
VEGF receptor-2 (KDR).";
Biochem. Biophys. Res. Commun. 252:743-746(1998).
[13]
FUNCTION IN ACTIVATION OF THE PHOSPHATIDYLINOSITOL 3-KINASE AND AKT1
SIGNALING PATHWAY.
PubMed=9804796; DOI=10.1074/jbc.273.46.30336;
Gerber H.P., McMurtrey A., Kowalski J., Yan M., Keyt B.A., Dixit V.,
Ferrara N.;
"Vascular endothelial growth factor regulates endothelial cell
survival through the phosphatidylinositol 3'-kinase/Akt signal
transduction pathway. Requirement for Flk-1/KDR activation.";
J. Biol. Chem. 273:30336-30343(1998).
[14]
FUNCTION IN NITRIC OXIDE RELEASE.
PubMed=10600473; DOI=10.1006/bbrc.1999.1729;
Kroll J., Waltenberger J.;
"A novel function of VEGF receptor-2 (KDR): rapid release of nitric
oxide in response to VEGF-A stimulation in endothelial cells.";
Biochem. Biophys. Res. Commun. 265:636-639(1999).
[15]
CATALYTIC ACTIVITY, CHARACTERIZATION OF VARIANT GLU-848,
PHOSPHORYLATION AT TYR-1054 AND TYR-1059, AND ENZYME REGULATION.
PubMed=10037737; DOI=10.1074/jbc.274.10.6453;
Kendall R.L., Rutledge R.Z., Mao X., Tebben A.J., Hungate R.W.,
Thomas K.A.;
"Vascular endothelial growth factor receptor KDR tyrosine kinase
activity is increased by autophosphorylation of two activation loop
tyrosine residues.";
J. Biol. Chem. 274:6453-6460(1999).
[16]
FUNCTION IN PHOSPHORYLATION OF PLCG1 AND PTK2/FAK1, INTERACTION WITH
VEGFA, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-996; TYR-1054 AND
TYR-1059, MUTAGENESIS OF TYR-996; TYR-1054 AND TYR-1059, SUBCELLULAR
LOCATION, AND ENZYME REGULATION.
PubMed=10102632; DOI=10.1038/sj.onc.1202478;
Dougher M., Terman B.I.;
"Autophosphorylation of KDR in the kinase domain is required for
maximal VEGF-stimulated kinase activity and receptor
internalization.";
Oncogene 18:1619-1627(1999).
[17]
INTERACTION WITH HIV-1 TAT.
PubMed=10590123; DOI=10.1128/JVI.74.1.344-353.2000;
Mitola S., Soldi R., Zanon I., Barra L., Gutierrez M.I., Berkhout B.,
Giacca M., Bussolino F.;
"Identification of specific molecular structures of human
immunodeficiency virus type 1 Tat relevant for its biological effects
on vascular endothelial cells.";
J. Virol. 74:344-353(2000).
[18]
FUNCTION IN ENDOTHELIAL CELL PROLIFERATION; PHOSPHORYLATION OF PLCG1
AND ACTIVATION OF MAP KINASES, PHOSPHORYLATION AT TYR-1175 AND
TYR-1214, AND MUTAGENESIS OF LYS-868 AND TYR-1175.
PubMed=11387210; DOI=10.1093/emboj/20.11.2768;
Takahashi T., Yamaguchi S., Chida K., Shibuya M.;
"A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-
A-dependent activation of PLC-gamma and DNA synthesis in vascular
endothelial cells.";
EMBO J. 20:2768-2778(2001).
[19]
UBIQUITINATION, FUNCTION IN NITRIC OXIDE PRODUCTION, SUBCELLULAR
LOCATION, AND INTERACTION WITH CBL.
PubMed=12649282; DOI=10.1074/jbc.M301410200;
Duval M., Bedard-Goulet S., Delisle C., Gratton J.P.;
"Vascular endothelial growth factor-dependent down-regulation of Flk-
1/KDR involves Cbl-mediated ubiquitination. Consequences on nitric
oxide production from endothelial cells.";
J. Biol. Chem. 278:20091-20097(2003).
[20]
INTERACTION WITH FLT4.
PubMed=12881528; DOI=10.1074/jbc.M304499200;
Dixelius J., Makinen T., Wirzenius M., Karkkainen M.J., Wernstedt C.,
Alitalo K., Claesson-Welsh L.;
"Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-
3) heterodimerization with VEGFR-2 in primary lymphatic endothelial
cells regulates tyrosine phosphorylation sites.";
J. Biol. Chem. 278:40973-40979(2003).
[21]
INTERACTION WITH SHB, AND FUNCTION IN CELL MIGRATION.
PubMed=15026417; DOI=10.1074/jbc.M312729200;
Holmqvist K., Cross M.J., Rolny C., Haegerkvist R., Rahimi N.,
Matsumoto T., Claesson-Welsh L., Welsh M.;
"The adaptor protein shb binds to tyrosine 1175 in vascular
endothelial growth factor (VEGF) receptor-2 and regulates VEGF-
dependent cellular migration.";
J. Biol. Chem. 279:22267-22275(2004).
[22]
SUBCELLULAR LOCATION, AND PHOSPHORYLATION.
PubMed=14991896; DOI=10.1002/path.1520;
Fox S.B., Turley H., Cheale M., Blazquez C., Roberts H., James N.,
Cook N., Harris A., Gatter K.;
"Phosphorylated KDR is expressed in the neoplastic and stromal
elements of human renal tumours and shuttles from cell membrane to
nucleus.";
J. Pathol. 202:313-320(2004).
[23]
INTERACTION WITH VEGFA AND VEGFD, PHOSPHORYLATION AT TYR-1054 AND
TYR-1059, FUNCTION IN VEGFA AND VEGFD SIGNALING; ACTIVATION OF
MAPK1/ERK2 AND MAPK3/ERK1; ACTIVATION OF AKT1; PHOSPHORYLATION OF
PLCG1 AND NOS3; MODULATION OF INTRACELLULAR CA(2+) LEVELS; CELL
SURVIVAL AND POSITIVE REGULATION OF CELL PROLIFERATION; CELL MIGRATION
AND ANGIOGENESIS, AND ENZYME REGULATION.
PubMed=15215251; DOI=10.1074/jbc.M401538200;
Jia H., Bagherzadeh A., Bicknell R., Duchen M.R., Liu D., Zachary I.;
"Vascular endothelial growth factor (VEGF)-D and VEGF-A differentially
regulate KDR-mediated signaling and biological function in vascular
endothelial cells.";
J. Biol. Chem. 279:36148-36157(2004).
[24]
FUNCTION IN CELL MIGRATION; PHOSPHORYLATION OF PLCG1; ACTIVATION OF
MAPK1/ERK2; MAPK3/ERK1 AND THE MAP KINASES AND IN REGULATION OF ACTIN
CYTOSKELETON REORGANIZATION, INTERACTION WITH SH2D2A/TSAD,
PHOSPHORYLATION AT TYR-951; TYR-1054; TYR-1059; TYR-1214; TYR-1305;
TYR-1309 AND TYR-1319, AND MUTAGENESIS OF TYR-951.
PubMed=15962004; DOI=10.1038/sj.emboj.7600709;
Matsumoto T., Bohman S., Dixelius J., Berge T., Dimberg A.,
Magnusson P., Wang L., Wikner C., Qi J.H., Wernstedt C., Wu J.,
Bruheim S., Mugishima H., Mukhopadhyay D., Spurkland A.,
Claesson-Welsh L.;
"VEGF receptor-2 Y951 signaling and a role for the adapter molecule
TSAd in tumor angiogenesis.";
EMBO J. 24:2342-2353(2005).
[25]
FUNCTION IN ENDOTHELIAL CELL MIGRATION; ACTIVATION OF MAP KINASES AND
IN PHOSPHORYLATION OF FYN; SRC AND NCK1, INTERACTION WITH GRB2; FYN
AND NCK1, AND MUTAGENESIS OF TYR-1214.
PubMed=16966330; DOI=10.1074/jbc.M603928200;
Lamalice L., Houle F., Huot J.;
"Phosphorylation of Tyr1214 within VEGFR-2 triggers the recruitment of
Nck and activation of Fyn leading to SAPK2/p38 activation and
endothelial cell migration in response to VEGF.";
J. Biol. Chem. 281:34009-34020(2006).
[26]
SUBCELLULAR LOCATION, UBIQUITINATION, AND DEGRADATION.
PubMed=17004325; DOI=10.1111/j.1600-0854.2006.00462.x;
Ewan L.C., Jopling H.M., Jia H., Mittar S., Bagherzadeh A.,
Howell G.J., Walker J.H., Zachary I.C., Ponnambalam S.;
"Intrinsic tyrosine kinase activity is required for vascular
endothelial growth factor receptor 2 ubiquitination, sorting and
degradation in endothelial cells.";
Traffic 7:1270-1282(2006).
[27]
FUNCTION IN ACTIVATION OF AKT1; PHOSPHORYLATION OF PLCG1 AND NOS3 AND
REGULATION OF NITRIC OXIDE PRODUCTION, PHOSPHORYLATION AT TYR-801, AND
MUTAGENESIS OF TYR-801.
PubMed=17303569; DOI=10.1074/jbc.M609048200;
Blanes M.G., Oubaha M., Rautureau Y., Gratton J.P.;
"Phosphorylation of tyrosine 801 of vascular endothelial growth factor
receptor-2 is necessary for Akt-dependent endothelial nitric-oxide
synthase activation and nitric oxide release from endothelial cells.";
J. Biol. Chem. 282:10660-10669(2007).
[28]
INTERACTION WITH DAB2IP.
PubMed=19033661; DOI=10.1172/JCI36168;
Zhang H., He Y., Dai S., Xu Z., Luo Y., Wan T., Luo D., Jones D.,
Tang S., Chen H., Sessa W.C., Min W.;
"AIP1 functions as an endogenous inhibitor of VEGFR2-mediated
signaling and inflammatory angiogenesis in mice.";
J. Clin. Invest. 118:3904-3916(2008).
[29]
PHOSPHORYLATION AT TYR-951; TYR-1175 AND TYR-1214, AND
DEPHOSPHORYLATION BY PTPRB.
PubMed=19136612; DOI=10.1096/fj.08-123810;
Mellberg S., Dimberg A., Bahram F., Hayashi M., Rennel E., Ameur A.,
Westholm J.O., Larsson E., Lindahl P., Cross M.J., Claesson-Welsh L.;
"Transcriptional profiling reveals a critical role for tyrosine
phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial
cell morphogenesis.";
FASEB J. 23:1490-1502(2009).
[30]
PHOSPHORYLATION AT TYR-801; TYR-951; TYR-996; TYR-1054; TYR-1059;
TYR-1175 AND TYR-1214; DEPHOSPHORYLATION AT TYR-951; TYR-996;
TYR-1054; TYR-1059; TYR-1175 AND TYR-1214 BY PTPRJ.
PubMed=18936167; DOI=10.1128/MCB.01374-08;
Chabot C., Spring K., Gratton J.P., Elchebly M., Royal I.;
"New role for the protein tyrosine phosphatase DEP-1 in Akt activation
and endothelial cell survival.";
Mol. Cell. Biol. 29:241-253(2009).
[31]
FUNCTION AS VEGFA RECEPTOR IN TUMOR ANGIOGENESIS, SUBCELLULAR
LOCATION, AND UBIQUITINATION.
PubMed=19834490; DOI=10.1038/cdd.2009.152;
Zhang Z., Neiva K.G., Lingen M.W., Ellis L.M., Nor J.E.;
"VEGF-dependent tumor angiogenesis requires inverse and reciprocal
regulation of VEGFR1 and VEGFR2.";
Cell Death Differ. 17:499-512(2010).
[32]
FUNCTION IN LYMPHANGIOGENESIS (ISOFORM 2).
PubMed=20179233; DOI=10.1158/1078-0432.CCR-09-1936;
Becker J., Pavlakovic H., Ludewig F., Wilting F., Weich H.A.,
Albuquerque R., Ambati J., Wilting J.;
"Neuroblastoma progression correlates with downregulation of the
lymphangiogenesis inhibitor sVEGFR-2.";
Clin. Cancer Res. 16:1431-1441(2010).
[33]
INTERACTION WITH VEGFC AND FLT4, SUBCELLULAR LOCATION, AND FUNCTION IN
ANGIOGENESIS.
PubMed=20224550; DOI=10.1038/emboj.2010.30;
Nilsson I., Bahram F., Li X., Gualandi L., Koch S., Jarvius M.,
Soderberg O., Anisimov A., Kholova I., Pytowski B., Baldwin M.,
Yla-Herttuala S., Alitalo K., Kreuger J., Claesson-Welsh L.;
"VEGF receptor 2/-3 heterodimers detected in situ by proximity
ligation on angiogenic sprouts.";
EMBO J. 29:1377-1388(2010).
[34]
SUBCELLULAR LOCATION.
PubMed=21539813; DOI=10.1016/j.bbrc.2011.04.093;
Jopling H.M., Howell G.J., Gamper N., Ponnambalam S.;
"The VEGFR2 receptor tyrosine kinase undergoes constitutive endosome-
to-plasma membrane recycling.";
Biochem. Biophys. Res. Commun. 410:170-176(2011).
[35]
FUNCTION IN LYMPHANGIOGENESIS, AND INTERACTION WITH FLT4 AND VEGFC.
PubMed=20705758; DOI=10.1182/blood-2010-02-267427;
Nakao S., Zandi S., Hata Y., Kawahara S., Arita R., Schering A.,
Sun D., Melhorn M.I., Ito Y., Lara-Castillo N., Ishibashi T.,
Hafezi-Moghadam A.;
"Blood vessel endothelial VEGFR-2 delays lymphangiogenesis: an
endogenous trapping mechanism links lymph- and angiogenesis.";
Blood 117:1081-1090(2011).
[36]
REVIEW ON ROLE IN ANGIOGENESIS.
PubMed=17002866; DOI=10.5483/BMBRep.2006.39.5.469;
Shibuya M.;
"Differential roles of vascular endothelial growth factor receptor-1
and receptor-2 in angiogenesis.";
J. Biochem. Mol. Biol. 39:469-478(2006).
[37]
REVIEW.
PubMed=17658244; DOI=10.1016/j.cellsig.2007.05.013;
Holmes K., Roberts O.L., Thomas A.M., Cross M.J.;
"Vascular endothelial growth factor receptor-2: structure, function,
intracellular signalling and therapeutic inhibition.";
Cell. Signal. 19:2003-2012(2007).
[38]
REVIEW ON STRUCTURE AND FUNCTION.
PubMed=18680722; DOI=10.1016/j.bbrc.2008.07.121;
Roskoski R. Jr.;
"VEGF receptor protein-tyrosine kinases: structure and regulation.";
Biochem. Biophys. Res. Commun. 375:287-291(2008).
[39]
REVIEW ON ROLE IN ANGIOGENESIS AND CANCER.
PubMed=19230644; DOI=10.1016/j.ceb.2008.12.012;
Lohela M., Bry M., Tammela T., Alitalo K.;
"VEGFs and receptors involved in angiogenesis versus
lymphangiogenesis.";
Curr. Opin. Cell Biol. 21:154-165(2009).
[40]
REVIEW ON LIGAND SPECIFICITY; FUNCTION; STRUCTURE; PHOSPHORYLATION AND
SIGNALING.
PubMed=19761875; DOI=10.1016/j.bbapap.2009.09.002;
Grunewald F.S., Prota A.E., Giese A., Ballmer-Hofer K.;
"Structure-function analysis of VEGF receptor activation and the role
of coreceptors in angiogenic signaling.";
Biochim. Biophys. Acta 1804:567-580(2010).
[41]
REVIEW ON ROLE IN ANGIOGENESIS AND CANCER.
PubMed=20462514; DOI=10.1016/j.bbcan.2010.04.004;
Guo S., Colbert L.S., Fuller M., Zhang Y., Gonzalez-Perez R.R.;
"Vascular endothelial growth factor receptor-2 in breast cancer.";
Biochim. Biophys. Acta 1806:108-121(2010).
[42]
REVIEW ON ROLE IN ANGIOGENESIS AND CANCER.
PubMed=21779435; DOI=10.1177/1947601910392987;
Shibuya M.;
"Tyrosine kinase receptor Flt/VEGFR family: its characterization
related to angiogenesis and cancer.";
Genes Cancer 1:1119-1123(2010).
[43]
REVIEW ON LIGAND SPECIFICITY; FUNCTION; STRUCTURE; PHOSPHORYLATION AND
SIGNALING.
PubMed=21711246; DOI=10.1042/BJ20110301;
Koch S., Tugues S., Li X., Gualandi L., Claesson-Welsh L.;
"Signal transduction by vascular endothelial growth factor
receptors.";
Biochem. J. 437:169-183(2011).
[44]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-982 AND SER-984, AND
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=21406692; DOI=10.1126/scisignal.2001570;
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
Blagoev B.;
"System-wide temporal characterization of the proteome and
phosphoproteome of human embryonic stem cell differentiation.";
Sci. Signal. 4:RS3-RS3(2011).
[45]
FUNCTION, AND INTERACTION WITH PDCD6.
PubMed=21893193; DOI=10.1016/j.cellsig.2011.08.013;
Rho S.B., Song Y.J., Lim M.C., Lee S.H., Kim B.R., Park S.Y.;
"Programmed cell death 6 (PDCD6) inhibits angiogenesis through
PI3K/mTOR/p70S6K pathway by interacting of VEGFR-2.";
Cell. Signal. 24:131-139(2012).
[46]
ENZYME REGULATION, REDOX-ACTIVE DISULFIDE BOND, AND MUTAGENESIS OF
CYS-1045.
PubMed=23199280; DOI=10.1089/ars.2012.4565;
Tao B.B., Liu S.Y., Zhang C.C., Fu W., Cai W.J., Wang Y., Shen Q.,
Wang M.J., Chen Y., Zhang L.J., Zhu Y.Z., Zhu Y.C.;
"VEGFR2 functions as an H(2)S-targeting receptor protein kinase with
its novel Cys1045-Cys1024 disulfide bond serving as a specific
molecular switch for hydrogen sulfide actions in vascular endothelial
cells.";
Antioxid. Redox Signal. 19:448-464(2013).
[47]
INTERACTION WITH ERN1, AND SUBCELLULAR LOCATION.
PubMed=23529610; DOI=10.1161/CIRCULATIONAHA.112.001337;
Zeng L., Xiao Q., Chen M., Margariti A., Martin D., Ivetic A., Xu H.,
Mason J., Wang W., Cockerill G., Mori K., Li J.Y., Chien S., Hu Y.,
Xu Q.;
"Vascular endothelial cell growth-activated XBP1 splicing in
endothelial cells is crucial for angiogenesis.";
Circulation 127:1712-1722(2013).
[48]
X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 806-1171, FUNCTION,
PHOSPHORYLATION AT TYR-1059, AND IDENTIFICATION BY MASS SPECTROMETRY.
PubMed=10368301; DOI=10.1016/S0969-2126(99)80042-2;
McTigue M.A., Wickersham J.A., Pinko C., Showalter R.E., Parast C.V.,
Tempczyk-Russell A., Gehring M.R., Mroczkowski B., Kan C.-C.,
Villafranca J.E., Appelt K.;
"Crystal structure of the kinase domain of human vascular endothelial
growth factor receptor 2: a key enzyme in angiogenesis.";
Structure 7:319-330(1999).
[49]
X-RAY CRYSTALLOGRAPHY (1.71 ANGSTROMS) OF 806-1171 IN COMPLEX WITH
SYNTHETIC INHIBITOR.
PubMed=15837294; DOI=10.1016/j.bmcl.2005.03.034;
Miyazaki Y., Matsunaga S., Tang J., Maeda Y., Nakano M.,
Philippe R.J., Shibahara M., Liu W., Sato H., Wang L., Nolte R.T.;
"Novel 4-amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual
inhibitors.";
Bioorg. Med. Chem. Lett. 15:2203-2207(2005).
[50]
X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 815-1171 IN COMPLEX WITH
SYNTHETIC INHIBITOR.
PubMed=17253678; DOI=10.1021/jm061107l;
Hodous B.L., Geuns-Meyer S.D., Hughes P.E., Albrecht B.K., Bellon S.,
Bready J., Caenepeel S., Cee V.J., Chaffee S.C., Coxon A., Emery M.,
Fretland J., Gallant P., Gu Y., Hoffman D., Johnson R.E., Kendall R.,
Kim J.L., Long A.M., Morrison M., Olivieri P.R., Patel V.F.,
Polverino A., Rose P., Tempest P., Wang L., Whittington D.A., Zhao H.;
"Evolution of a highly selective and potent 2-(pyridin-2-yl)-1,3,5-
triazine Tie-2 kinase inhibitor.";
J. Med. Chem. 50:611-626(2007).
[51]
X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 806-1171 IN COMPLEX WITH
SYNTHETIC INHIBITOR, AND FUNCTION.
PubMed=18529047; DOI=10.1021/jm8001185;
Peifer C., Selig R., Kinkel K., Ott D., Totzke F., Schaechtele C.,
Heidenreich R., Roecken M., Schollmeyer D., Laufer S.;
"Design, synthesis, and biological evaluation of novel 3-aryl-4-(1H-
indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as vascular endothelial
growth factor receptor (VEGF-R) inhibitors.";
J. Med. Chem. 51:3814-3824(2008).
[52]
X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 657-764, SUBUNIT,
AUTOPHOSPHORYLATION, FUNCTION IN VEGFA SIGNALING AND ACTIVATION OF
MAPK1/ERK2 AND MAPK3/ERK1, AND MUTAGENESIS OF ARG-726 AND ASP-731.
PubMed=20080685; DOI=10.1073/pnas.0914052107;
Yang Y., Xie P., Opatowsky Y., Schlessinger J.;
"Direct contacts between extracellular membrane-proximal domains are
required for VEGF receptor activation and cell signaling.";
Proc. Natl. Acad. Sci. U.S.A. 107:1906-1911(2010).
[53]
X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 120-326 IN COMPLEX WITH
VEGFC, INTERACTION WITH VEGFC, DOMAIN, DISULFIDE BONDS, AND
GLYCOSYLATION AT ASN-143; ASN-245 AND ASN-318.
PubMed=20145116; DOI=10.1073/pnas.0914318107;
Leppanen V.M., Prota A.E., Jeltsch M., Anisimov A., Kalkkinen N.,
Strandin T., Lankinen H., Goldman A., Ballmer-Hofer K., Alitalo K.;
"Structural determinants of growth factor binding and specificity by
VEGF receptor 2.";
Proc. Natl. Acad. Sci. U.S.A. 107:2425-2430(2010).
[54]
X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 220-338 IN COMPLEX WITH
ANTIBODY FRAGMENT, DISULFIDE BOND, AND GLYCOSYLATION AT ASN-245 AND
ASN-318.
PubMed=21827946; DOI=10.1016/j.str.2011.01.019;
Franklin M.C., Navarro E.C., Wang Y., Patel S., Singh P., Zhang Y.,
Persaud K., Bari A., Griffith H., Shen L., Balderes P., Kussie P.;
"The structural basis for the function of two anti-VEGF receptor 2
antibodies.";
Structure 19:1097-1107(2011).
[55]
VARIANT HCI SER-1147.
PubMed=11807987; DOI=10.1002/gcc.10028;
Walter J.W., North P.E., Waner M., Mizeracki A., Blei F.,
Walker J.W.T., Reinisch J.F., Marchuk D.A.;
"Somatic mutation of vascular endothelial growth factor receptors in
juvenile hemangioma.";
Genes Chromosomes Cancer 33:295-303(2002).
[56]
VARIANTS [LARGE SCALE ANALYSIS] LEU-275 AND ARG-873.
PubMed=16959974; DOI=10.1126/science.1133427;
Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
Vogelstein B., Kinzler K.W., Velculescu V.E.;
"The consensus coding sequences of human breast and colorectal
cancers.";
Science 314:268-274(2006).
[57]
VARIANT HCI ARG-482, AND VARIANTS [LARGE SCALE ANALYSIS] ARG-2;
MET-136; GLY-248; ILE-297; VAL-462; HIS-472; ARG-539; MET-689; ASN-814
AND THR-1065.
PubMed=17344846; DOI=10.1038/nature05610;
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
"Patterns of somatic mutation in human cancer genomes.";
Nature 446:153-158(2007).
[58]
VARIANT HCI ARG-482.
PubMed=18931684; DOI=10.1038/nm.1877;
Jinnin M., Medici D., Park L., Limaye N., Liu Y., Boscolo E.,
Bischoff J., Vikkula M., Boye E., Olsen B.R.;
"Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2
signaling in infantile hemangioma.";
Nat. Med. 14:1236-1246(2008).
-!- FUNCTION: Tyrosine-protein kinase that acts as a cell-surface
receptor for VEGFA, VEGFC and VEGFD. Plays an essential role in
the regulation of angiogenesis, vascular development, vascular
permeability, and embryonic hematopoiesis. Promotes proliferation,
survival, migration and differentiation of endothelial cells.
Promotes reorganization of the actin cytoskeleton. Isoforms
lacking a transmembrane domain, such as isoform 2 and isoform 3,
may function as decoy receptors for VEGFA, VEGFC and/or VEGFD.
Isoform 2 plays an important role as negative regulator of
VEGFA- and VEGFC-mediated lymphangiogenesis by limiting the amount
of free VEGFA and/or VEGFC and preventing their binding to FLT4.
Modulates FLT1 and FLT4 signaling by forming heterodimers. Binding
of vascular growth factors to isoform 1 leads to the activation of
several signaling cascades. Activation of PLCG1 leads to the
production of the cellular signaling molecules diacylglycerol and
inositol 1,4,5-trisphosphate and the activation of protein kinase
C. Mediates activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP
kinase signaling pathway, as well as of the AKT1 signaling
pathway. Mediates phosphorylation of PIK3R1, the regulatory
subunit of phosphatidylinositol 3-kinase, reorganization of the
actin cytoskeleton and activation of PTK2/FAK1. Required for
VEGFA-mediated induction of NOS2 and NOS3, leading to the
production of the signaling molecule nitric oxide (NO) by
endothelial cells. Phosphorylates PLCG1. Promotes phosphorylation
of FYN, NCK1, NOS3, PIK3R1, PTK2/FAK1 and SRC.
{ECO:0000269|PubMed:10102632, ECO:0000269|PubMed:10368301,
ECO:0000269|PubMed:10600473, ECO:0000269|PubMed:11387210,
ECO:0000269|PubMed:12649282, ECO:0000269|PubMed:1417831,
ECO:0000269|PubMed:15026417, ECO:0000269|PubMed:15215251,
ECO:0000269|PubMed:15962004, ECO:0000269|PubMed:16966330,
ECO:0000269|PubMed:17303569, ECO:0000269|PubMed:18529047,
ECO:0000269|PubMed:19668192, ECO:0000269|PubMed:19834490,
ECO:0000269|PubMed:20080685, ECO:0000269|PubMed:20224550,
ECO:0000269|PubMed:20705758, ECO:0000269|PubMed:21893193,
ECO:0000269|PubMed:7929439, ECO:0000269|PubMed:9160888,
ECO:0000269|PubMed:9804796, ECO:0000269|PubMed:9837777}.
-!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
[protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE-
ProRule:PRU10028, ECO:0000269|PubMed:10037737,
ECO:0000269|PubMed:10102632}.
-!- ENZYME REGULATION: Present in an inactive conformation in the
absence of bound ligand. Binding of VEGFA, VEGFC or VEGFD leads to
dimerization and activation by autophosphorylation on tyrosine
residues. Inhibited by the small molecule PTK inhibitor SU5614
((3Z)-5-Chloro-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylene]-1,3-
dihydro-2H-indol-2-one). May be regulated by hydrogen sulfide
(H(2)S) levels via a H(2)S-sensitive intracellular disulfide bond.
{ECO:0000269|PubMed:10037737, ECO:0000269|PubMed:10102632,
ECO:0000269|PubMed:15215251, ECO:0000269|PubMed:23199280}.
-!- SUBUNIT: Homodimer in the presence of bound dimeric VEGFA, VEGFC
or VEGFD ligands; monomeric in the absence of bound ligands. Can
also form heterodimers with FLT1/VEGFR1 and FLT4/VEGFR2. Interacts
(tyrosine phosphorylated) with LFYN, NCK1, PLCG1. Interacts
(tyrosine-phosphorylated active form preferentially) with DAB2IP
(via C2 domain and active form preferentially); the interaction
occurs at the late phase of VEGFA response and inhibits KDR/VEGFR2
activity. Interacts with SHBSH2D2A/TSAD, GRB2, MYOF, CBL and
PDCD6. Interacts with HIV-1 Tat (PubMed:10102632, PubMed:10590123,
PubMed:12649282, PubMed:12881528, PubMed:1417831, PubMed:15026417,
PubMed:15215251, PubMed:15837294, PubMed:15962004,
PubMed:16966330, PubMed:17253678, PubMed:18529047,
PubMed:18593464, PubMed:19033661, PubMed:19668192,
PubMed:20080685, PubMed:20145116, PubMed:20224550,
PubMed:20705758, PubMed:21827946, PubMed:21893193,
PubMed:9160888). Interacts (via C-terminus domain) with ERN1 (via
kinase domain); the interaction is facilitated in a XBP1 isoform
1- and vascular endothelial growth factor (VEGF)-dependent manner
in endothelial cells (PubMed:23529610).
{ECO:0000269|PubMed:10102632, ECO:0000269|PubMed:10590123,
ECO:0000269|PubMed:12649282, ECO:0000269|PubMed:12881528,
ECO:0000269|PubMed:1417831, ECO:0000269|PubMed:15026417,
ECO:0000269|PubMed:15215251, ECO:0000269|PubMed:15837294,
ECO:0000269|PubMed:15962004, ECO:0000269|PubMed:16966330,
ECO:0000269|PubMed:17253678, ECO:0000269|PubMed:18529047,
ECO:0000269|PubMed:18593464, ECO:0000269|PubMed:19033661,
ECO:0000269|PubMed:19668192, ECO:0000269|PubMed:20080685,
ECO:0000269|PubMed:20145116, ECO:0000269|PubMed:20224550,
ECO:0000269|PubMed:20705758, ECO:0000269|PubMed:21827946,
ECO:0000269|PubMed:21893193, ECO:0000269|PubMed:23529610,
ECO:0000269|PubMed:9160888}.
-!- INTERACTION:
P46108:CRK; NbExp=2; IntAct=EBI-1005487, EBI-886;
P35916:FLT4; NbExp=5; IntAct=EBI-1005487, EBI-1005467;
O60565:GREM1; NbExp=4; IntAct=EBI-1005487, EBI-944395;
P98160:HSPG2; NbExp=5; IntAct=EBI-1005487, EBI-947664;
P17301:ITGA2; NbExp=2; IntAct=EBI-1005487, EBI-702960;
P09382:LGALS1; NbExp=3; IntAct=EBI-1005487, EBI-1048875;
P08581:MET; NbExp=3; IntAct=EBI-1005487, EBI-1039152;
P16333:NCK1; NbExp=3; IntAct=EBI-1005487, EBI-389883;
O14786:NRP1; NbExp=2; IntAct=EBI-1005487, EBI-1187100;
O75340:PDCD6; NbExp=4; IntAct=EBI-1005487, EBI-352915;
Q12913:PTPRJ; NbExp=4; IntAct=EBI-1005487, EBI-2264500;
P12931:SRC; NbExp=2; IntAct=EBI-1005487, EBI-621482;
P15692:VEGFA; NbExp=5; IntAct=EBI-1005487, EBI-1026643;
P15692-4:VEGFA; NbExp=6; IntAct=EBI-1005487, EBI-1026691;
-!- SUBCELLULAR LOCATION: Cell junction {ECO:0000250}. Endoplasmic
reticulum {ECO:0000269|PubMed:23529610}. Note=Localized with RAP1A
at cell-cell junctions (By similarity). Colocalizes with ERN1 and
XBP1 in the endoplasmic reticulum in endothelial cells in a
vascular endothelial growth factor (VEGF)-dependent manner
(PubMed:23529610). {ECO:0000250, ECO:0000269|PubMed:23529610}.
-!- SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I
membrane protein. Cytoplasm. Nucleus. Cytoplasmic vesicle. Early
endosome. Note=Detected on caveolae-enriched lipid rafts at the
cell surface. Is recycled from the plasma membrane to endosomes
and back again. Phosphorylation triggered by VEGFA binding
promotes internalization and subsequent degradation. VEGFA binding
triggers internalization and translocation to the nucleus.
-!- SUBCELLULAR LOCATION: Isoform 2: Secreted {ECO:0000305}.
-!- SUBCELLULAR LOCATION: Isoform 3: Secreted.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=3;
Name=1; Synonyms=mbVegfr-2;
IsoId=P35968-1; Sequence=Displayed;
Name=2; Synonyms=sVegfr-2;
IsoId=P35968-2; Sequence=VSP_041988, VSP_041989;
Name=3; Synonyms=VEGFR2-712;
IsoId=P35968-3; Sequence=VSP_041990, VSP_041991;
-!- TISSUE SPECIFICITY: Detected in cornea (at protein level). Widely
expressed. {ECO:0000269|PubMed:19668192}.
-!- DOMAIN: The second and third Ig-like C2-type (immunoglobulin-like)
domains are sufficient for VEGFC binding.
{ECO:0000269|PubMed:20145116}.
-!- PTM: N-glycosylated. {ECO:0000269|PubMed:20145116,
ECO:0000269|PubMed:21827946, ECO:0000269|PubMed:9160888}.
-!- PTM: Ubiquitinated. Tyrosine phosphorylation of the receptor
promotes its poly-ubiquitination, leading to its degradation via
the proteasome or lysosomal proteases.
{ECO:0000269|PubMed:12649282, ECO:0000269|PubMed:17004325,
ECO:0000269|PubMed:19834490}.
-!- PTM: Autophosphorylated on tyrosine residues upon ligand binding.
Autophosphorylation occurs in trans, i.e. one subunit of the
dimeric receptor phosphorylates tyrosine residues on the other
subunit. Phosphorylation at Tyr-951 is important for interaction
with SH2D2A/TSAD and VEGFA-mediated reorganization of the actin
cytoskeleton. Phosphorylation at Tyr-1175 is important for
interaction with PLCG1 and SHB. Phosphorylation at Tyr-1214 is
important for interaction with NCK1 and FYN. Dephosphorylated by
PTPRB. Dephosphorylated by PTPRJ at Tyr-951, Tyr-996, Tyr-1054,
Tyr-1059, Tyr-1175 and Tyr-1214. {ECO:0000269|PubMed:10037737,
ECO:0000269|PubMed:10102632, ECO:0000269|PubMed:10368301,
ECO:0000269|PubMed:11387210, ECO:0000269|PubMed:15215251,
ECO:0000269|PubMed:15962004, ECO:0000269|PubMed:18936167,
ECO:0000269|PubMed:19136612}.
-!- PTM: The inhibitory disulfide bond between Cys-1024 and Cys-1045
may serve as a specific molecular switch for H(2)S-induced
modification that regulates VEGFR2 function.
-!- DISEASE: Hemangioma, capillary infantile (HCI) [MIM:602089]: A
condition characterized by dull red, firm, dome-shaped
hemangiomas, sharply demarcated from surrounding skin, usually
presenting at birth or occurring within the first two or three
months of life. They result from highly proliferative, localized
growth of capillary endothelium and generally undergo regression
and involution without scarring. {ECO:0000269|PubMed:11807987,
ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:18931684}.
Note=Disease susceptibility is associated with variations
affecting the gene represented in this entry.
-!- DISEASE: Note=Plays a major role in tumor angiogenesis. In case of
HIV-1 infection, the interaction with extracellular viral Tat
protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
-!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
kinase family. CSF-1/PDGF receptor subfamily.
{ECO:0000255|PROSITE-ProRule:PRU00159}.
-----------------------------------------------------------------------
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EMBL; EU826563; ACF47599.1; -; mRNA.
EMBL; FJ899739; ACR78514.1; -; mRNA.
EMBL; AF035121; AAB88005.1; -; mRNA.
EMBL; AF063658; AAC16450.1; -; mRNA.
EMBL; AC021220; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AC111194; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; BC131822; AAI31823.1; -; mRNA.
EMBL; L04947; AAA59459.1; -; mRNA.
EMBL; X61656; CAA43837.1; -; mRNA.
EMBL; X89776; CAA61916.1; -; Genomic_DNA.
CCDS; CCDS3497.1; -. [P35968-1]
PIR; JC1402; JC1402.
RefSeq; NP_002244.1; NM_002253.2. [P35968-1]
UniGene; Hs.479756; -.
PDB; 1VR2; X-ray; 2.40 A; A=806-1171.
PDB; 1Y6A; X-ray; 2.10 A; A=806-1171.
PDB; 1Y6B; X-ray; 2.10 A; A=806-1171.
PDB; 1YWN; X-ray; 1.71 A; A=806-1171.
PDB; 2M59; NMR; -; A/B=759-795.
PDB; 2MET; NMR; -; A/B/C=759-795.
PDB; 2MEU; NMR; -; A/B=759-795.
PDB; 2OH4; X-ray; 2.05 A; A=806-1171.
PDB; 2P2H; X-ray; 1.95 A; A=815-1171.
PDB; 2P2I; X-ray; 2.40 A; A/B=815-1171.
PDB; 2QU5; X-ray; 2.95 A; A=815-1171.
PDB; 2QU6; X-ray; 2.10 A; A/B=815-1171.
PDB; 2RL5; X-ray; 2.65 A; A=815-1171.
PDB; 2X1W; X-ray; 2.70 A; L/M/N/O=120-326.
PDB; 2X1X; X-ray; 3.10 A; R=120-326.
PDB; 2XIR; X-ray; 1.50 A; A=806-1171.
PDB; 3B8Q; X-ray; 2.75 A; A/B=815-1171.
PDB; 3B8R; X-ray; 2.70 A; A/B=815-1171.
PDB; 3BE2; X-ray; 1.75 A; A=815-1171.
PDB; 3C7Q; X-ray; 2.10 A; A=806-1171.
PDB; 3CJF; X-ray; 2.15 A; A=806-1168.
PDB; 3CJG; X-ray; 2.25 A; A=806-1168.
PDB; 3CP9; X-ray; 2.50 A; A/B=815-1171.
PDB; 3CPB; X-ray; 2.70 A; A/B=815-1171.
PDB; 3CPC; X-ray; 2.40 A; A/B=815-1171.
PDB; 3DTW; X-ray; 2.90 A; A/B=815-1171.
PDB; 3EFL; X-ray; 2.20 A; A/B=815-1171.
PDB; 3EWH; X-ray; 1.60 A; A=815-1171.
PDB; 3KVQ; X-ray; 2.70 A; A=657-764.
PDB; 3S35; X-ray; 2.20 A; X=220-338.
PDB; 3S36; X-ray; 3.20 A; X=220-338.
PDB; 3S37; X-ray; 2.70 A; X=220-338.
PDB; 3U6J; X-ray; 2.15 A; A=815-1171.
PDB; 3V2A; X-ray; 3.20 A; R=2-764.
PDB; 3V6B; X-ray; 3.20 A; R=132-548.
PDB; 3VHE; X-ray; 1.55 A; A=811-1169.
PDB; 3VHK; X-ray; 2.49 A; A=806-1171.
PDB; 3VID; X-ray; 2.30 A; A=813-1168.
PDB; 3VNT; X-ray; 1.64 A; A=806-1171.
PDB; 3VO3; X-ray; 1.52 A; A=806-1171.
PDB; 3WZD; X-ray; 1.57 A; A=814-1172.
PDB; 3WZE; X-ray; 1.90 A; A=814-1172.
PDB; 4AG8; X-ray; 1.95 A; A=806-1171.
PDB; 4AGC; X-ray; 2.00 A; A=787-1171.
PDB; 4AGD; X-ray; 2.81 A; A=787-1171.
PDB; 4ASD; X-ray; 2.03 A; A=787-1171.
PDB; 4ASE; X-ray; 1.83 A; A=787-1171.
PDB; 5EW3; X-ray; 2.50 A; A/B=806-1171.
PDBsum; 1VR2; -.
PDBsum; 1Y6A; -.
PDBsum; 1Y6B; -.
PDBsum; 1YWN; -.
PDBsum; 2M59; -.
PDBsum; 2MET; -.
PDBsum; 2MEU; -.
PDBsum; 2OH4; -.
PDBsum; 2P2H; -.
PDBsum; 2P2I; -.
PDBsum; 2QU5; -.
PDBsum; 2QU6; -.
PDBsum; 2RL5; -.
PDBsum; 2X1W; -.
PDBsum; 2X1X; -.
PDBsum; 2XIR; -.
PDBsum; 3B8Q; -.
PDBsum; 3B8R; -.
PDBsum; 3BE2; -.
PDBsum; 3C7Q; -.
PDBsum; 3CJF; -.
PDBsum; 3CJG; -.
PDBsum; 3CP9; -.
PDBsum; 3CPB; -.
PDBsum; 3CPC; -.
PDBsum; 3DTW; -.
PDBsum; 3EFL; -.
PDBsum; 3EWH; -.
PDBsum; 3KVQ; -.
PDBsum; 3S35; -.
PDBsum; 3S36; -.
PDBsum; 3S37; -.
PDBsum; 3U6J; -.
PDBsum; 3V2A; -.
PDBsum; 3V6B; -.
PDBsum; 3VHE; -.
PDBsum; 3VHK; -.
PDBsum; 3VID; -.
PDBsum; 3VNT; -.
PDBsum; 3VO3; -.
PDBsum; 3WZD; -.
PDBsum; 3WZE; -.
PDBsum; 4AG8; -.
PDBsum; 4AGC; -.
PDBsum; 4AGD; -.
PDBsum; 4ASD; -.
PDBsum; 4ASE; -.
PDBsum; 5EW3; -.
ProteinModelPortal; P35968; -.
SMR; P35968; -.
BioGrid; 109992; 43.
DIP; DIP-486N; -.
IntAct; P35968; 33.
MINT; MINT-127732; -.
STRING; 9606.ENSP00000263923; -.
BindingDB; P35968; -.
ChEMBL; CHEMBL279; -.
DrugBank; DB07528; 3-(2-aminoquinazolin-6-yl)-4-methyl-1-[3-(trifluoromethyl)phenyl]pyridin-2(1H)-one.
DrugBank; DB06938; 4-[[2-[[4-chloro-3-(trifluoromethyl)phenyl]amino]-3H-benzimidazol-5-yl]oxy]-N-methyl-pyridine-2-carboxamide.
DrugBank; DB06080; ABT-869.
DrugBank; DB06626; Axitinib.
DrugBank; DB04849; AZD2171.
DrugBank; DB08875; Cabozantinib.
DrugBank; DB05198; CYC116.
DrugBank; DB06101; IMC-1C11.
DrugBank; DB09078; Lenvatinib.
DrugBank; DB07183; N-(4-phenoxyphenyl)-2-[(pyridin-4-ylmethyl)amino]nicotinamide.
DrugBank; DB09079; Nintedanib.
DrugBank; DB06589; Pazopanib.
DrugBank; DB08901; Ponatinib.
DrugBank; DB05578; Ramucirumab.
DrugBank; DB08896; Regorafenib.
DrugBank; DB00398; Sorafenib.
DrugBank; DB01268; Sunitinib.
DrugBank; DB05075; TG100801.
DrugBank; DB04879; Vatalanib.
DrugBank; DB05153; XL184.
DrugBank; DB05146; XL820.
DrugBank; DB05030; XL880.
DrugBank; DB05014; XL999.
GuidetoPHARMACOLOGY; 1813; -.
iPTMnet; P35968; -.
PhosphoSitePlus; P35968; -.
BioMuta; KDR; -.
DMDM; 9087218; -.
EPD; P35968; -.
MaxQB; P35968; -.
PaxDb; P35968; -.
PeptideAtlas; P35968; -.
PRIDE; P35968; -.
DNASU; 3791; -.
Ensembl; ENST00000263923; ENSP00000263923; ENSG00000128052. [P35968-1]
GeneID; 3791; -.
KEGG; hsa:3791; -.
UCSC; uc003has.4; human. [P35968-1]
CTD; 3791; -.
DisGeNET; 3791; -.
GeneCards; KDR; -.
HGNC; HGNC:6307; KDR.
HPA; CAB004028; -.
MalaCards; KDR; -.
MIM; 191306; gene.
MIM; 602089; phenotype.
neXtProt; NX_P35968; -.
OpenTargets; ENSG00000128052; -.
Orphanet; 91415; Familial capillary hemangioma.
PharmGKB; PA30086; -.
eggNOG; KOG0200; Eukaryota.
eggNOG; COG0515; LUCA.
GeneTree; ENSGT00760000118923; -.
HOVERGEN; HBG053432; -.
InParanoid; P35968; -.
KO; K05098; -.
OMA; MFFWLLL; -.
OrthoDB; EOG091G01TL; -.
PhylomeDB; P35968; -.
TreeFam; TF325768; -.
BRENDA; 2.7.10.1; 2681.
Reactome; R-HSA-194306; Neurophilin interactions with VEGF and VEGFR.
Reactome; R-HSA-195399; VEGF binds to VEGFR leading to receptor dimerization.
Reactome; R-HSA-216083; Integrin cell surface interactions.
Reactome; R-HSA-3928663; EPHA-mediated growth cone collapse.
Reactome; R-HSA-4420097; VEGFA-VEGFR2 Pathway.
Reactome; R-HSA-5218921; VEGFR2 mediated cell proliferation.
SignaLink; P35968; -.
SIGNOR; P35968; -.
EvolutionaryTrace; P35968; -.
GeneWiki; Kinase_insert_domain_receptor; -.
GenomeRNAi; 3791; -.
PRO; PR:P35968; -.
Proteomes; UP000005640; Chromosome 4.
Bgee; ENSG00000128052; -.
CleanEx; HS_KDR; -.
ExpressionAtlas; P35968; baseline and differential.
Genevisible; P35968; HS.
GO; GO:0030054; C:cell junction; ISS:UniProtKB.
GO; GO:0005769; C:early endosome; ISS:BHF-UCL.
GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
GO; GO:0005768; C:endosome; IDA:UniProtKB.
GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
GO; GO:0045121; C:membrane raft; IDA:UniProtKB.
GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
GO; GO:0097443; C:sorting endosome; ISS:BHF-UCL.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0019838; F:growth factor binding; IPI:BHF-UCL.
GO; GO:0051879; F:Hsp90 protein binding; TAS:BHF-UCL.
GO; GO:0005178; F:integrin binding; IPI:BHF-UCL.
GO; GO:0004713; F:protein tyrosine kinase activity; IDA:UniProtKB.
GO; GO:0004716; F:signal transducer, downstream of receptor, with protein tyrosine kinase activity; TAS:BHF-UCL.
GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; TAS:BHF-UCL.
GO; GO:0038085; F:vascular endothelial growth factor binding; IPI:BHF-UCL.
GO; GO:0005021; F:vascular endothelial growth factor-activated receptor activity; IDA:UniProtKB.
GO; GO:0001525; P:angiogenesis; TAS:BHF-UCL.
GO; GO:0035584; P:calcium-mediated signaling using intracellular calcium source; IMP:UniProtKB.
GO; GO:0002042; P:cell migration involved in sprouting angiogenesis; ISS:BHF-UCL.
GO; GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; IDA:UniProtKB.
GO; GO:0035162; P:embryonic hemopoiesis; ISS:UniProtKB.
GO; GO:0003158; P:endothelium development; ISS:UniProtKB.
GO; GO:0030198; P:extracellular matrix organization; TAS:Reactome.
GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IDA:UniProtKB.
GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; ISS:BHF-UCL.
GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
GO; GO:0045766; P:positive regulation of angiogenesis; IMP:UniProtKB.
GO; GO:0030335; P:positive regulation of cell migration; IDA:BHF-UCL.
GO; GO:0008284; P:positive regulation of cell proliferation; IDA:BHF-UCL.
GO; GO:0038033; P:positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway; IDA:BHF-UCL.
GO; GO:0010595; P:positive regulation of endothelial cell migration; IMP:BHF-UCL.
GO; GO:0001938; P:positive regulation of endothelial cell proliferation; IMP:UniProtKB.
GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:UniProtKB.
GO; GO:0051894; P:positive regulation of focal adhesion assembly; IDA:BHF-UCL.
GO; GO:0016239; P:positive regulation of macroautophagy; IGI:MGI.
GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:UniProtKB.
GO; GO:0051901; P:positive regulation of mitochondrial depolarization; IGI:MGI.
GO; GO:0090141; P:positive regulation of mitochondrial fission; IGI:MGI.
GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; IDA:UniProtKB.
GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IDA:UniProtKB.
GO; GO:0050927; P:positive regulation of positive chemotaxis; IDA:BHF-UCL.
GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:UniProtKB.
GO; GO:2001214; P:positive regulation of vasculogenesis; ISS:UniProtKB.
GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
GO; GO:0008360; P:regulation of cell shape; IDA:BHF-UCL.
GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; TAS:ProtInc.
GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; IDA:UniProtKB.
GO; GO:0001570; P:vasculogenesis; ISS:UniProtKB.
GO; GO:0016032; P:viral process; IEA:UniProtKB-KW.
Gene3D; 2.60.40.10; -; 8.
InterPro; IPR007110; Ig-like_dom.
InterPro; IPR013783; Ig-like_fold.
InterPro; IPR013098; Ig_I-set.
InterPro; IPR003599; Ig_sub.
InterPro; IPR003598; Ig_sub2.
InterPro; IPR013151; Immunoglobulin.
InterPro; IPR011009; Kinase-like_dom.
InterPro; IPR000719; Prot_kinase_dom.
InterPro; IPR017441; Protein_kinase_ATP_BS.
InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
InterPro; IPR008266; Tyr_kinase_AS.
InterPro; IPR020635; Tyr_kinase_cat_dom.
InterPro; IPR001824; Tyr_kinase_rcpt_3_CS.
InterPro; IPR009136; VEGFR2_rcpt.
PANTHER; PTHR24416:SF378; PTHR24416:SF378; 1.
Pfam; PF07679; I-set; 2.
Pfam; PF00047; ig; 1.
Pfam; PF07714; Pkinase_Tyr; 1.
PRINTS; PR01834; VEGFRECEPTR2.
SMART; SM00409; IG; 7.
SMART; SM00408; IGc2; 5.
SMART; SM00219; TyrKc; 1.
SUPFAM; SSF48726; SSF48726; 7.
SUPFAM; SSF56112; SSF56112; 2.
PROSITE; PS50835; IG_LIKE; 5.
PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PROSITE; PS00240; RECEPTOR_TYR_KIN_III; 1.
1: Evidence at protein level;
3D-structure; Alternative splicing; Angiogenesis; ATP-binding;
Cell junction; Cell membrane; Complete proteome; Cytoplasm;
Cytoplasmic vesicle; Developmental protein; Differentiation;
Disulfide bond; Endoplasmic reticulum; Endosome; Glycoprotein;
Host-virus interaction; Immunoglobulin domain; Kinase; Membrane;
Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Receptor;
Reference proteome; Repeat; Secreted; Signal; Transferase;
Transmembrane; Transmembrane helix; Tyrosine-protein kinase;
Ubl conjugation.
SIGNAL 1 19 {ECO:0000255}.
CHAIN 20 1356 Vascular endothelial growth factor
receptor 2.
/FTId=PRO_0000016771.
TOPO_DOM 20 764 Extracellular. {ECO:0000255}.
TRANSMEM 765 785 Helical. {ECO:0000255}.
TOPO_DOM 786 1356 Cytoplasmic. {ECO:0000255}.
DOMAIN 46 110 Ig-like C2-type 1.
DOMAIN 141 207 Ig-like C2-type 2.
DOMAIN 224 320 Ig-like C2-type 3.
DOMAIN 328 414 Ig-like C2-type 4.
DOMAIN 421 548 Ig-like C2-type 5.
DOMAIN 551 660 Ig-like C2-type 6.
DOMAIN 667 753 Ig-like C2-type 7.
DOMAIN 834 1162 Protein kinase. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
NP_BIND 840 848 ATP. {ECO:0000305}.
ACT_SITE 1028 1028 Proton acceptor. {ECO:0000255|PROSITE-
ProRule:PRU00159, ECO:0000255|PROSITE-
ProRule:PRU10028}.
BINDING 868 868 ATP. {ECO:0000305}.
SITE 1175 1175 Interaction with SHB. {ECO:0000250}.
MOD_RES 801 801 Phosphotyrosine.
{ECO:0000269|PubMed:17303569,
ECO:0000269|PubMed:18936167}.
MOD_RES 951 951 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:15962004,
ECO:0000269|PubMed:18936167,
ECO:0000269|PubMed:19136612}.
MOD_RES 982 982 Phosphoserine.
{ECO:0000244|PubMed:21406692}.
MOD_RES 984 984 Phosphoserine.
{ECO:0000244|PubMed:21406692}.
MOD_RES 996 996 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:10102632,
ECO:0000269|PubMed:18936167}.
MOD_RES 1054 1054 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:10037737,
ECO:0000269|PubMed:10102632,
ECO:0000269|PubMed:15215251,
ECO:0000269|PubMed:15962004,
ECO:0000269|PubMed:18936167}.
MOD_RES 1059 1059 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:10037737,
ECO:0000269|PubMed:10102632,
ECO:0000269|PubMed:10368301,
ECO:0000269|PubMed:15215251,
ECO:0000269|PubMed:15962004,
ECO:0000269|PubMed:18936167}.
MOD_RES 1175 1175 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:11387210,
ECO:0000269|PubMed:18936167,
ECO:0000269|PubMed:19136612}.
MOD_RES 1214 1214 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:11387210,
ECO:0000269|PubMed:15962004,
ECO:0000269|PubMed:18936167,
ECO:0000269|PubMed:19136612}.
MOD_RES 1231 1231 Phosphoserine.
{ECO:0000250|UniProtKB:P35918}.
MOD_RES 1235 1235 Phosphoserine.
{ECO:0000250|UniProtKB:P35918}.
MOD_RES 1238 1238 Phosphothreonine.
{ECO:0000250|UniProtKB:P35918}.
MOD_RES 1305 1305 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:15962004}.
MOD_RES 1309 1309 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:15962004}.
MOD_RES 1319 1319 Phosphotyrosine; by autocatalysis.
{ECO:0000269|PubMed:15962004}.
CARBOHYD 46 46 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 66 66 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 96 96 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 143 143 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:20145116}.
CARBOHYD 158 158 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 245 245 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:20145116,
ECO:0000269|PubMed:21827946}.
CARBOHYD 318 318 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:20145116,
ECO:0000269|PubMed:21827946}.
CARBOHYD 374 374 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 395 395 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 511 511 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 523 523 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 580 580 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 613 613 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 619 619 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 631 631 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 675 675 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 704 704 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 721 721 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
DISULFID 53 103 {ECO:0000255|PROSITE-ProRule:PRU00114}.
DISULFID 150 200
DISULFID 246 307
DISULFID 445 530 {ECO:0000255|PROSITE-ProRule:PRU00114}.
DISULFID 571 642 {ECO:0000255|PROSITE-ProRule:PRU00114}.
DISULFID 688 737 {ECO:0000255|PROSITE-ProRule:PRU00114}.
DISULFID 1024 1045 Redox-active.
VAR_SEQ 663 678 ERVAPTITGNLENQTT -> GRETILDHCAEAVGMP (in
isoform 2).
{ECO:0000303|PubMed:19668192}.
/FTId=VSP_041988.
VAR_SEQ 679 1356 Missing (in isoform 2).
{ECO:0000303|PubMed:19668192}.
/FTId=VSP_041989.
VAR_SEQ 712 712 G -> E (in isoform 3).
{ECO:0000303|PubMed:18593464}.
/FTId=VSP_041990.
VAR_SEQ 713 1356 Missing (in isoform 3).
{ECO:0000303|PubMed:18593464}.
/FTId=VSP_041991.
VARIANT 2 2 Q -> R (in a lung adenocarcinoma sample;
somatic mutation).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_042053.
VARIANT 136 136 V -> M (in dbSNP:rs35636987).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_042054.
VARIANT 248 248 A -> G (in a renal clear cell carcinoma
sample; somatic mutation).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_042055.
VARIANT 275 275 R -> L (in a colorectal cancer sample;
somatic mutation).
{ECO:0000269|PubMed:16959974}.
/FTId=VAR_036126.
VARIANT 297 297 V -> I (in dbSNP:rs2305948).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_022071.
VARIANT 462 462 L -> V (in dbSNP:rs56286620).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_042056.
VARIANT 472 472 Q -> H (in dbSNP:rs1870377).
{ECO:0000269|PubMed:15489334,
ECO:0000269|PubMed:17344846}.
/FTId=VAR_020353.
VARIANT 482 482 C -> R (in HCI; associated with disease
susceptibility; expression of FLT1 in
hemangioma endothelial cells is markedly
reduced and KDR activity is increased
compared to controls; low FLT1 expression
in hemangioma cells is caused by reduced
activity of a pathway involving ITGB1,
ANTXR1, KDR and NFATC2IP; the mutation
predicts to result in loss-of-function
and disruption of the normal association
of these molecules; dbSNP:rs34231037).
{ECO:0000269|PubMed:17344846,
ECO:0000269|PubMed:18931684}.
/FTId=VAR_042057.
VARIANT 539 539 G -> R (in dbSNP:rs55716939).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_042058.
VARIANT 689 689 T -> M (in dbSNP:rs34038364).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_042059.
VARIANT 814 814 D -> N (in dbSNP:rs35603373).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_042060.
VARIANT 848 848 V -> E (strongly reduced
autophosphorylation and kinase activity;
dbSNP:rs1139776).
{ECO:0000269|PubMed:10037737,
ECO:0000269|PubMed:1656371}.
/FTId=VAR_046679.
VARIANT 873 873 G -> R (in a colorectal cancer sample;
somatic mutation).
{ECO:0000269|PubMed:16959974}.
/FTId=VAR_036127.
VARIANT 952 952 V -> I (in dbSNP:rs13129474).
/FTId=VAR_046680.
VARIANT 1065 1065 A -> T (in dbSNP:rs56302315).
{ECO:0000269|PubMed:17344846}.
/FTId=VAR_042061.
VARIANT 1147 1147 P -> S (in HCI; somatic mutation;
dbSNP:rs121917766).
{ECO:0000269|PubMed:11807987}.
/FTId=VAR_063147.
MUTAGEN 726 726 R->A: Strongly reduced
autophosphorylation and activation of MAP
kinases. {ECO:0000269|PubMed:20080685}.
MUTAGEN 731 731 D->A: Strongly reduced
autophosphorylation and activation of MAP
kinases. {ECO:0000269|PubMed:20080685}.
MUTAGEN 801 801 Y->F: Abolishes stimulation of nitric
oxide synthesis.
{ECO:0000269|PubMed:17303569}.
MUTAGEN 868 868 K->M: Loss of enzyme activity.
{ECO:0000269|PubMed:11387210}.
MUTAGEN 951 951 Y->F: Abolishes reorganization of the
actin cytoskeleton and cell migration in
response to VEGFA.
{ECO:0000269|PubMed:15962004}.
MUTAGEN 996 996 Y->F: Strongly reduced
autophosphorylation. Reduces
phosphorylation of PLCG1.
{ECO:0000269|PubMed:10102632}.
MUTAGEN 1045 1045 C->A: Significantly higher kinase
activity. {ECO:0000269|PubMed:23199280}.
MUTAGEN 1054 1054 Y->F: Strongly reduced
autophosphorylation. Abolishes
phosphorylation of downstream signaling
proteins; when associated with F-1059.
{ECO:0000269|PubMed:10102632}.
MUTAGEN 1059 1059 Y->F: Strongly reduced
autophosphorylation. Abolishes
phosphorylation of downstream signaling
proteins; when associated with F-1054.
{ECO:0000269|PubMed:10102632}.
MUTAGEN 1175 1175 Y->F: Abolishes phosphorylation of PLCG1
and MAP kinases in response to VEGFA.
{ECO:0000269|PubMed:11387210}.
MUTAGEN 1214 1214 Y->F: Loss of phosphorylation site.
Abolishes reorganization of the actin
cytoskeleton in response to VEGFA.
{ECO:0000269|PubMed:16966330}.
CONFLICT 2 2 Q -> E (in Ref. 4; AAC16450).
{ECO:0000305}.
CONFLICT 772 772 A -> T (in Ref. 7; AAA59459/CAA43837).
{ECO:0000305}.
CONFLICT 787 787 R -> G (in Ref. 7; AAA59459/CAA43837).
{ECO:0000305}.
CONFLICT 835 835 K -> N (in Ref. 7; AAA59459/CAA43837).
{ECO:0000305}.
CONFLICT 1347 1347 S -> T (in Ref. 7; AAA59459/CAA43837).
{ECO:0000305}.
STRAND 134 138 {ECO:0000244|PDB:2X1W}.
STRAND 145 148 {ECO:0000244|PDB:2X1W}.
STRAND 152 154 {ECO:0000244|PDB:2X1W}.
STRAND 159 164 {ECO:0000244|PDB:2X1W}.
TURN 165 167 {ECO:0000244|PDB:2X1W}.
STRAND 168 170 {ECO:0000244|PDB:2X1W}.
STRAND 174 176 {ECO:0000244|PDB:2X1W}.
STRAND 178 180 {ECO:0000244|PDB:2X1W}.
TURN 181 183 {ECO:0000244|PDB:2X1W}.
STRAND 184 188 {ECO:0000244|PDB:2X1W}.
HELIX 189 191 {ECO:0000244|PDB:2X1W}.
TURN 192 194 {ECO:0000244|PDB:2X1W}.
STRAND 196 202 {ECO:0000244|PDB:2X1W}.
STRAND 214 218 {ECO:0000244|PDB:2X1W}.
STRAND 223 230 {ECO:0000244|PDB:3S35}.
STRAND 234 238 {ECO:0000244|PDB:3S35}.
STRAND 242 250 {ECO:0000244|PDB:3S35}.
STRAND 257 261 {ECO:0000244|PDB:3S35}.
HELIX 269 272 {ECO:0000244|PDB:3S35}.
STRAND 279 282 {ECO:0000244|PDB:3S35}.
STRAND 285 296 {ECO:0000244|PDB:3S35}.
HELIX 299 301 {ECO:0000244|PDB:3S35}.
STRAND 303 310 {ECO:0000244|PDB:3S35}.
STRAND 315 328 {ECO:0000244|PDB:3S35}.
STRAND 676 679 {ECO:0000244|PDB:3KVQ}.
STRAND 684 687 {ECO:0000244|PDB:3KVQ}.
STRAND 697 706 {ECO:0000244|PDB:3KVQ}.
STRAND 713 716 {ECO:0000244|PDB:3KVQ}.
TURN 717 720 {ECO:0000244|PDB:3KVQ}.
STRAND 721 724 {ECO:0000244|PDB:3KVQ}.
HELIX 729 731 {ECO:0000244|PDB:3KVQ}.
STRAND 733 740 {ECO:0000244|PDB:3KVQ}.
STRAND 746 755 {ECO:0000244|PDB:3KVQ}.
HELIX 760 794 {ECO:0000244|PDB:2M59}.
STRAND 804 806 {ECO:0000244|PDB:4AGC}.
TURN 808 810 {ECO:0000244|PDB:4ASE}.
TURN 813 815 {ECO:0000244|PDB:3VHE}.
HELIX 817 819 {ECO:0000244|PDB:2XIR}.
HELIX 824 827 {ECO:0000244|PDB:2XIR}.
HELIX 831 833 {ECO:0000244|PDB:2XIR}.
STRAND 834 842 {ECO:0000244|PDB:2XIR}.
STRAND 844 858 {ECO:0000244|PDB:2XIR}.
STRAND 862 870 {ECO:0000244|PDB:2XIR}.
HELIX 876 892 {ECO:0000244|PDB:2XIR}.
STRAND 901 905 {ECO:0000244|PDB:2XIR}.
STRAND 907 910 {ECO:0000244|PDB:3WZD}.
STRAND 913 917 {ECO:0000244|PDB:2XIR}.
HELIX 924 929 {ECO:0000244|PDB:2XIR}.
TURN 930 933 {ECO:0000244|PDB:3VO3}.
STRAND 934 936 {ECO:0000244|PDB:2XIR}.
TURN 995 998 {ECO:0000244|PDB:3VO3}.
HELIX 1002 1021 {ECO:0000244|PDB:2XIR}.
STRAND 1024 1026 {ECO:0000244|PDB:4AGC}.
HELIX 1031 1033 {ECO:0000244|PDB:2XIR}.
STRAND 1034 1036 {ECO:0000244|PDB:2XIR}.
HELIX 1038 1040 {ECO:0000244|PDB:2XIR}.
STRAND 1042 1044 {ECO:0000244|PDB:2XIR}.
HELIX 1048 1050 {ECO:0000244|PDB:2XIR}.
TURN 1053 1055 {ECO:0000244|PDB:2XIR}.
STRAND 1059 1062 {ECO:0000244|PDB:2XIR}.
STRAND 1065 1067 {ECO:0000244|PDB:2XIR}.
HELIX 1069 1071 {ECO:0000244|PDB:2XIR}.
HELIX 1074 1079 {ECO:0000244|PDB:2XIR}.
HELIX 1084 1099 {ECO:0000244|PDB:2XIR}.
STRAND 1105 1108 {ECO:0000244|PDB:3C7Q}.
HELIX 1113 1121 {ECO:0000244|PDB:2XIR}.
HELIX 1133 1142 {ECO:0000244|PDB:2XIR}.
HELIX 1147 1149 {ECO:0000244|PDB:2XIR}.
HELIX 1153 1167 {ECO:0000244|PDB:2XIR}.
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


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