VGFR3_HUMAN
ID VGFR3_HUMAN Reviewed; 1363 AA.
AC P35916; A8K6L4; B5A926; Q16067; Q86W07; Q86W08;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 16-NOV-2011, sequence version 3.
DT 03-AUG-2022, entry version 225.
DE RecName: Full=Vascular endothelial growth factor receptor 3;
DE Short=VEGFR-3;
DE EC=2.7.10.1;
DE AltName: Full=Fms-like tyrosine kinase 4;
DE Short=FLT-4;
DE AltName: Full=Tyrosine-protein kinase receptor FLT4;
DE Flags: Precursor;
GN Name=FLT4; Synonyms=VEGFR3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
RX PubMed=1327515;
RA Pajusola K., Aprelikova O., Korhonen J., Kaipainen A., Pertovaara L.,
RA Alitalo R., Alitalo K.;
RT "FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and
RT is expressed in multiple human tissues and cell lines.";
RL Cancer Res. 52:5738-5743(1992).
RN [2]
RP ERRATUM OF PUBMED:1327515.
RA Pajusola K., Aprelikova O., Korhonen J., Kaipainen A., Pertovaara L.,
RA Alitalo R., Alitalo K.;
RL Cancer Res. 53:3845-3845(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=1319394; DOI=10.1016/0888-7543(92)90277-y;
RA Galland F., Karamysheva A., Mattei M.-G., Rosnet O., Marchetto S.,
RA Birnbaum D.;
RT "Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase
RT gene.";
RL Genomics 13:475-478(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANTS GLN-890 AND HIS-1146.
RC TISSUE=Placenta;
RX PubMed=8386825;
RA Galland F., Karamysheva A., Pebusque M.-J., Borg J.-P., Rottapel R.,
RA Dubreuil P., Rosnet O., Birnbaum D.;
RT "The FLT4 gene encodes a transmembrane tyrosine kinase related to the
RT vascular endothelial growth factor receptor.";
RL Oncogene 8:1233-1240(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), INTERACTION WITH VEGFC,
RP PHOSPHORYLATION, AND FUNCTION IN CELL PROLIFERATION.
RX PubMed=8700872; DOI=10.1073/pnas.93.5.1988;
RA Lee J., Gray A., Yuan J., Luoh S.-M., Avraham H., Wood W.I.;
RT "Vascular endothelial growth factor-related protein: a ligand and specific
RT activator of the tyrosine kinase receptor Flt4.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:1988-1992(1996).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), INTERACTION WITH VEGFD, 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 [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND VARIANTS GLN-890 AND
RP HIS-1146.
RA Lian Z., Feitelson M.;
RL Submitted (FEB-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT GLN-890.
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 761-1190.
RX PubMed=1310071;
RA Aprelikova O., Pajusola K., Partanen J., Armstrong E., Alitalo R.,
RA Bailey S.K., McMahon J., Wasmuth J., Huebner K., Alitalo K.;
RT "FLT4, a novel class III receptor tyrosine kinase in chromosome 5q33-
RT qter.";
RL Cancer Res. 52:746-748(1992).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1293-1363 (ISOFORM 1), AND ALTERNATIVE
RP SPLICING.
RX PubMed=7692369;
RA Pajusola K., Aprelikova O., Armstrong E., Morris S., Alitalo K.;
RT "Two human FLT4 receptor tyrosine kinase isoforms with distinct carboxy
RT terminal tails are produced by alternative processing of primary
RT transcripts.";
RL Oncogene 8:2931-2937(1993).
RN [12]
RP PROTEIN SEQUENCE OF 25-39.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally verified
RT cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [13]
RP CATALYTIC ACTIVITY, GLYCOSYLATION, AND SUBCELLULAR LOCATION.
RX PubMed=7898938;
RA Borg J.P., deLapeyriere O., Noguchi T., Rottapel R., Dubreuil P.,
RA Birnbaum D.;
RT "Biochemical characterization of two isoforms of FLT4, a VEGF receptor-
RT related tyrosine kinase.";
RL Oncogene 10:973-984(1995).
RN [14]
RP FUNCTION IN CELL PROLIFERATION AND PHOSPHORYLATION OF SHC1,
RP CHARACTERIZATION OF ISOFORM 1 AND ISOFORM 2, INTERACTION WITH SHC1 AND
RP GRB2, AUTOPHOSPHORYLATION, MUTAGENESIS OF TYR-1333; TYR-1337 AND TYR-1363,
RP AND TISSUE SPECIFICITY.
RX PubMed=7675451;
RA Fournier E., Dubreuil P., Birnbaum D., Borg J.P.;
RT "Mutation at tyrosine residue 1337 abrogates ligand-dependent transforming
RT capacity of the FLT4 receptor.";
RL Oncogene 11:921-931(1995).
RN [15]
RP INTERACTION WITH VEGFD, FUNCTION AS VEGFD RECEPTOR, AND
RP AUTOPHOSPHORYLATION.
RX PubMed=9435229; DOI=10.1073/pnas.95.2.548;
RA Achen M.G., Jeltsch M., Kukk E., Maekinen T., Vitali A., Wilks A.F.,
RA Alitalo K., Stacker S.A.;
RT "Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine
RT kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4).";
RL Proc. Natl. Acad. Sci. U.S.A. 95:548-553(1998).
RN [16]
RP FUNCTION AS RECEPTOR FOR VEGFC AND VEGFD IN CELL SURVIVAL; PROLIFERATION
RP AND MIGRATION, AND FUNCTION IN ACTIVATION OF PROTEIN KINASE C; AKT1;
RP PIK3R1; MAPK1/ERK2 AND MAPK3/ERK1.
RX PubMed=11532940; DOI=10.1093/emboj/20.17.4762;
RA Makinen T., Veikkola T., Mustjoki S., Karpanen T., Catimel B., Nice E.C.,
RA Wise L., Mercer A., Kowalski H., Kerjaschki D., Stacker S.A., Achen M.G.,
RA Alitalo K.;
RT "Isolated lymphatic endothelial cells transduce growth, survival and
RT migratory signals via the VEGF-C/D receptor VEGFR-3.";
RL EMBO J. 20:4762-4773(2001).
RN [17]
RP INTERACTION WITH KDR, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION,
RP CHARACTERIZATION OF VARIANT LMPHM1 PRO-1041, MUTAGENESIS OF LYS-879;
RP TYR-1230; TYR-1231; TYR-1265; TYR-1333; TYR-1337 AND TYR-1363, AND
RP PHOSPHORYLATION AT TYR-1230; TYR-1231; TYR-1265; TYR-1333; TYR-1337 AND
RP TYR-1363.
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-3)
RT heterodimerization with VEGFR-2 in primary lymphatic endothelial cells
RT regulates tyrosine phosphorylation sites.";
RL J. Biol. Chem. 278:40973-40979(2003).
RN [18]
RP FUNCTION IN KDR SIGNALING AND IN ANGIOGENESIS, INTERACTION WITH KDR, AND
RP PHOSPHORYLATION.
RX PubMed=15474514; DOI=10.1016/j.bbrc.2004.08.237;
RA Alam A., Herault J.P., Barron P., Favier B., Fons P., Delesque-Touchard N.,
RA Senegas I., Laboudie P., Bonnin J., Cassan C., Savi P., Ruggeri B.,
RA Carmeliet P., Bono F., Herbert J.M.;
RT "Heterodimerization with vascular endothelial growth factor receptor-2
RT (VEGFR-2) is necessary for VEGFR-3 activity.";
RL Biochem. Biophys. Res. Commun. 324:909-915(2004).
RN [19]
RP FUNCTION IN CELL SURVIVAL, PHOSPHORYLATION IN RESPONSE TO OXIDATIVE STRESS,
RP INTERACTION WITH PIK3R1; SHC1; GRB2; PTPN11 AND PLCG1, ACTIVITY REGULATION
RP BY MAZ51, AND CHARACTERIZATION OF VARIANT LMPHM1 ARG-857.
RX PubMed=15102829; DOI=10.1074/jbc.m314015200;
RA Wang J.F., Zhang X., Groopman J.E.;
RT "Activation of vascular endothelial growth factor receptor-3 and its
RT downstream signaling promote cell survival under oxidative stress.";
RL J. Biol. Chem. 279:27088-27097(2004).
RN [20]
RP FUNCTION IN ACTIVATION OF AKT1; MAPK1/ERK2; MAPK3/ERK1 AND MAPK8, FUNCTION
RP IN PROMOTING CELL SURVIVAL; PROLIFERATION AND MIGRATION, CHARACTERIZATION
RP OF ISOFORM 1 AND ISOFORM 2, INTERACTION WITH CRK AND GRB2, PHOSPHORYLATION
RP AT TYR-1063; TYR-1068; TYR-1230; TYR-1231 AND TYR-1337, AND MUTAGENESIS OF
RP TYR-1063; TYR-1068; TYR-1230 AND TYR-1231.
RX PubMed=16076871; DOI=10.1182/blood-2005-04-1388;
RA Salameh A., Galvagni F., Bardelli M., Bussolino F., Oliviero S.;
RT "Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation,
RT migration, and survival of endothelial cells through the activation of ERK,
RT AKT, and JNK pathways.";
RL Blood 106:3423-3431(2005).
RN [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-527.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [22]
RP FUNCTION IN PROMOTING CELL SURVIVAL, INTERACTION WITH PTK2/FAK1, AND
RP SUBCELLULAR LOCATION.
RX PubMed=16452200; DOI=10.1158/0008-5472.can-05-1661;
RA Garces C.A., Kurenova E.V., Golubovskaya V.M., Cance W.G.;
RT "Vascular endothelial growth factor receptor-3 and focal adhesion kinase
RT bind and suppress apoptosis in breast cancer cells.";
RL Cancer Res. 66:1446-1454(2006).
RN [23]
RP FUNCTION IN LYMPHANGIOGENESIS.
RX PubMed=17210781; DOI=10.1096/fj.06-6656com;
RA Goldman J., Rutkowski J.M., Shields J.D., Pasquier M.C., Cui Y.,
RA Schmokel H.G., Willey S., Hicklin D.J., Pytowski B., Swartz M.A.;
RT "Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult
RT lymphangiogenesis.";
RL FASEB J. 21:1003-1012(2007).
RN [24]
RP ROLE IN CANCER, FUNCTION AS VEGFC RECEPTOR IN TUMOR LYMPHANGIOGENESIS; CELL
RP PROLIFERATION; CELL SURVIVAL; IN ACTIVATION OF PIK3R1; AKT1 AND MAP KINASES
RP AND IN UP-REGULATION OF VEGFA AND VEGFC EXPRESSION, ACTIVITY REGULATION,
RP AND AUTOPHOSPHORYLATION.
RX PubMed=19779139; DOI=10.2353/ajpath.2009.081139;
RA Matsuura M., Onimaru M., Yonemitsu Y., Suzuki H., Nakano T., Ishibashi H.,
RA Shirasuna K., Sueishi K.;
RT "Autocrine loop between vascular endothelial growth factor (VEGF)-C and
RT VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in
RT oral squamoid cancer cells.";
RL Am. J. Pathol. 175:1709-1721(2009).
RN [25]
RP ROLE IN CANCER, AND INTERACTION WITH PTK2/FAK1.
RX PubMed=19610651; DOI=10.1021/jm900159g;
RA Kurenova E.V., Hunt D.L., He D., Magis A.T., Ostrov D.A., Cance W.G.;
RT "Small molecule chloropyramine hydrochloride (C4) targets the binding site
RT of focal adhesion kinase and vascular endothelial growth factor receptor 3
RT and suppresses breast cancer growth in vivo.";
RL J. Med. Chem. 52:4716-4724(2009).
RN [26]
RP INTERACTION WITH PTPN14.
RX PubMed=20826270; DOI=10.1016/j.ajhg.2010.08.008;
RA Au A.C., Hernandez P.A., Lieber E., Nadroo A.M., Shen Y.M., Kelley K.A.,
RA Gelb B.D., Diaz G.A.;
RT "Protein tyrosine phosphatase PTPN14 is a regulator of lymphatic function
RT and choanal development in humans.";
RL Am. J. Hum. Genet. 87:436-444(2010).
RN [27]
RP PHOSPHORYLATION AT TYR-830; TYR-833; TYR-853; TYR-1063; TYR-1068; TYR-1333
RP AND TYR-1337, IDENTIFICATION IN A COMPLEX WITH SRC AND ITGB1, MUTAGENESIS
RP OF TYR-1063; TYR-1068 AND TYR-1337, ACTIVITY REGULATION BY MAZ51,
RP INTERACTION WITH ITGB1; CRK AND SHC1, FUNCTION IN ACTIVATION OF MAPK8 AND
RP IN REGULATION OF ANGIOGENIC SPROUTING, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RX PubMed=20431062; DOI=10.1161/circresaha.109.206326;
RA Galvagni F., Pennacchini S., Salameh A., Rocchigiani M., Neri F.,
RA Orlandini M., Petraglia F., Gotta S., Sardone G.L., Matteucci G.,
RA Terstappen G.C., Oliviero S.;
RT "Endothelial cell adhesion to the extracellular matrix induces c-Src-
RT dependent VEGFR-3 phosphorylation without the activation of the receptor
RT intrinsic kinase activity.";
RL Circ. Res. 106:1839-1848(2010).
RN [28]
RP INTERACTION WITH KDR, FUNCTION IN MODULATING KDR SIGNALING AND IN
RP ANGIOGENESIS, AND TISSUE SPECIFICITY.
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 ligation on
RT angiogenic sprouts.";
RL EMBO J. 29:1377-1388(2010).
RN [29]
RP FUNCTION IN ACTIVATION OF SIGNALING PATHWAYS, AND SUBCELLULAR LOCATION.
RX PubMed=20445537; DOI=10.1038/nature09002;
RA Wang Y., Nakayama M., Pitulescu M.E., Schmidt T.S., Bochenek M.L.,
RA Sakakibara A., Adams S., Davy A., Deutsch U., Luthi U., Barberis A.,
RA Benjamin L.E., Makinen T., Nobes C.D., Adams R.H.;
RT "Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis.";
RL Nature 465:483-486(2010).
RN [30]
RP FUNCTION IN LYMPHANGIOGENESIS.
RX PubMed=21273538; DOI=10.1167/iovs.10-6408;
RA Yuen D., Pytowski B., Chen L.;
RT "Combined blockade of VEGFR-2 and VEGFR-3 inhibits inflammatory
RT lymphangiogenesis in early and middle stages.";
RL Invest. Ophthalmol. Vis. Sci. 52:2593-2597(2011).
RN [31]
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 [32]
RP REVIEW ON ROLE IN LYMPHANGIOGENESIS 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 lymphangiogenesis.";
RL Curr. Opin. Cell Biol. 21:154-165(2009).
RN [33]
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 receptors.";
RL Biochem. J. 437:169-183(2011).
RN [34]
RP REVIEW ON FUNCTION IN LYMPHANGIOGENESIS AND ROLE IN CANCER.
RX PubMed=21196198; DOI=10.2741/3715;
RA Al-Rawi M.A., Jiang W.G.;
RT "Lymphangiogenesis and cancer metastasis.";
RL Front. Biosci. 16:723-739(2011).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 23-229 AND 330-553 IN COMPLEX
RP WITH VEGFC, GLYCOSYLATION AT ASN-33; ASN-104; ASN-166; ASN-411 AND ASN-515,
RP DISULFIDE BOND, INTERACTION WITH VEGFC, MUTAGENESIS OF THR-446; LYS-516 AND
RP ARG-737, AUTOPHOSPHORYLATION, HOMODIMER, AND DOMAIN.
RX PubMed=23878260; DOI=10.1073/pnas.1301415110;
RA Leppanen V.M., Tvorogov D., Kisko K., Prota A.E., Jeltsch M., Anisimov A.,
RA Markovic-Mueller S., Stuttfeld E., Goldie K.N., Ballmer-Hofer K.,
RA Alitalo K.;
RT "Structural and mechanistic insights into VEGF receptor 3 ligand binding
RT and activation.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:12960-12965(2013).
RN [36]
RP VARIANT LMPHM1 LEU-1114.
RX PubMed=9817924; DOI=10.1093/hmg/7.13.2073;
RA Ferrell R.E., Levinson K.L., Esman J.H., Kimak M.A., Lawrence E.C.,
RA Barmada M.M., Finegold D.N.;
RT "Hereditary lymphedema: evidence for linkage and genetic heterogeneity.";
RL Hum. Mol. Genet. 7:2073-2078(1998).
RN [37]
RP INVOLVEMENT IN LMPHM1, AND CHARACTERIZATION OF VARIANT LMPHM1 ARG-1035.
RX PubMed=10856194; DOI=10.1086/303019;
RA Irrthum A., Karkkainen M.J., Devriendt K., Alitalo K., Vikkula M.;
RT "Congenital hereditary lymphedema caused by a mutation that inactivates
RT VEGFR3 tyrosine kinase.";
RL Am. J. Hum. Genet. 67:295-301(2000).
RN [38]
RP VARIANTS LMPHM1 ARG-857; PRO-1041; PRO-1044 AND LEU-1114, VARIANT SER-641,
RP AND CHARACTERIZATION OF VARIANTS.
RX PubMed=10835628; DOI=10.1038/75997;
RA Karkkainen M.J., Ferrell R.E., Lawrence E.C., Kimak M.A., Levinson K.L.,
RA McTigue M.A., Alitalo K., Finegold D.N.;
RT "Missense mutations interfere with VEGFR-3 signalling in primary
RT lymphoedema.";
RL Nat. Genet. 25:153-159(2000).
RN [39]
RP VARIANTS HCI SER-954 AND SER-1137, AND VARIANTS ALA-494; GLN-890 AND
RP HIS-1146.
RX PubMed=11807987; DOI=10.1002/gcc.10028;
RA Walter J.W., North P.E., Waner M., Mizeracki A., Blei F., Walker J.W.T.,
RA 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 [40]
RP VARIANTS LMPHM1 MET-878; THR-1086 AND PHE-1108 DEL, VARIANT GLN-1035, AND
RP INVOLVEMENT IN LMPHM1.
RX PubMed=16965327; DOI=10.1111/j.1399-0004.2006.00687.x;
RA Ghalamkarpour A., Morlot S., Raas-Rothschild A., Utkus A., Mulliken J.B.,
RA Boon L.M., Vikkula M.;
RT "Hereditary lymphedema type I associated with VEGFR3 mutation: the first de
RT novo case and atypical presentations.";
RL Clin. Genet. 70:330-335(2006).
RN [41]
RP VARIANT LMPHM1 LYS-1106, AND INVOLVEMENT IN LMPHM1.
RX PubMed=16924388; DOI=10.1007/s10038-006-0031-3;
RA Spiegel R., Ghalamkarpour A., Daniel-Spiegel E., Vikkula M., Shalev S.A.;
RT "Wide clinical spectrum in a family with hereditary lymphedema type I due
RT to a novel missense mutation in VEGFR3.";
RL J. Hum. Genet. 51:846-850(2006).
RN [42]
RP VARIANT LMPHM1 LEU-1020.
RX PubMed=17458866; DOI=10.1002/ajmg.a.31703;
RA Butler M.G., Dagenais S.L., Rockson S.G., Glover T.W.;
RT "A novel VEGFR3 mutation causes Milroy disease.";
RL Am. J. Med. Genet. A 143A:1212-1217(2007).
RN [43]
RP VARIANTS [LARGE SCALE ANALYSIS] ASP-149; CYS-378; ALA-494; SER-527;
RP SER-641; TYR-868; ILE-1010; GLN-1031; ASN-1049; GLN-1075 AND HIS-1146.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [44]
RP VARIANT LMPHM1 THR-855, AND CHARACTERIZATION OF VARIANT LMPHM1 THR-855.
RX PubMed=19289394; DOI=10.1136/jmg.2008.064469;
RA Ghalamkarpour A., Holnthoner W., Saharinen P., Boon L.M., Mulliken J.B.,
RA Alitalo K., Vikkula M.;
RT "Recessive primary congenital lymphoedema caused by a VEGFR3 mutation.";
RL J. Med. Genet. 46:399-404(2009).
RN [45]
RP VARIANT LMPHM1 CYS-1235.
RX PubMed=26091405; DOI=10.1089/lrb.2014.0044;
RA Melikhan-Revzin S., Kurolap A., Dagan E., Mory A., Gershoni-Baruch R.;
RT "A novel missense mutation in FLT4 causes autosomal recessive hereditary
RT lymphedema.";
RL Lymphat. Res. Biol. 13:107-111(2015).
RN [46]
RP VARIANTS CHTD7 82-ARG--TYR-1363 DEL; 361-TYR--TYR-1363 DEL;
RP 736-GLN--TYR-1363 DEL AND 999-GLN--TYR-1363 DEL, AND INVOLVEMENT IN CHTD7.
RX PubMed=28991257; DOI=10.1038/ng.3970;
RA Jin S.C., Homsy J., Zaidi S., Lu Q., Morton S., DePalma S.R., Zeng X.,
RA Qi H., Chang W., Sierant M.C., Hung W.C., Haider S., Zhang J., Knight J.,
RA Bjornson R.D., Castaldi C., Tikhonoa I.R., Bilguvar K., Mane S.M.,
RA Sanders S.J., Mital S., Russell M.W., Gaynor J.W., Deanfield J.,
RA Giardini A., Porter G.A. Jr., Srivastava D., Lo C.W., Shen Y.,
RA Watkins W.S., Yandell M., Yost H.J., Tristani-Firouzi M., Newburger J.W.,
RA Roberts A.E., Kim R., Zhao H., Kaltman J.R., Goldmuntz E., Chung W.K.,
RA Seidman J.G., Gelb B.D., Seidman C.E., Lifton R.P., Brueckner M.;
RT "Contribution of rare inherited and de novo variants in 2,871 congenital
RT heart disease probands.";
RL Nat. Genet. 49:1593-1601(2017).
RN [47]
RP VARIANTS CHTD7 GLU-741 DEL; 833-TYR--TYR-1363 DEL; VAL-1173 AND
RP 1192-GLN--TYR-1363 DEL, AND INVOLVEMENT IN CHTD7.
RX PubMed=30232381; DOI=10.1038/s41436-018-0260-9;
RA Reuter M.S., Jobling R., Chaturvedi R.R., Manshaei R., Costain G.,
RA Heung T., Curtis M., Hosseini S.M., Liston E., Lowther C., Oechslin E.,
RA Sticht H., Thiruvahindrapuram B., Mil S.V., Wald R.M., Walker S.,
RA Marshall C.R., Silversides C.K., Scherer S.W., Kim R.H., Bassett A.S.;
RT "Haploinsufficiency of vascular endothelial growth factor related signaling
RT genes is associated with tetralogy of Fallot.";
RL Genet. Med. 21:1001-1007(2019).
CC -!- FUNCTION: Tyrosine-protein kinase that acts as a cell-surface receptor
CC for VEGFC and VEGFD, and plays an essential role in adult
CC lymphangiogenesis and in the development of the vascular network and
CC the cardiovascular system during embryonic development. Promotes
CC proliferation, survival and migration of endothelial cells, and
CC regulates angiogenic sprouting. Signaling by activated FLT4 leads to
CC enhanced production of VEGFC, and to a lesser degree VEGFA, thereby
CC creating a positive feedback loop that enhances FLT4 signaling.
CC Modulates KDR signaling by forming heterodimers. The secreted isoform 3
CC may function as a decoy receptor for VEGFC and/or VEGFD and play an
CC important role as a negative regulator of VEGFC-mediated
CC lymphangiogenesis and angiogenesis. Binding of vascular growth factors
CC to isoform 1 or isoform 2 leads to the activation of several signaling
CC cascades; isoform 2 seems to be less efficient in signal transduction,
CC because it has a truncated C-terminus and therefore lacks several
CC phosphorylation sites. Mediates activation of the MAPK1/ERK2,
CC MAPK3/ERK1 signaling pathway, of MAPK8 and the JUN signaling pathway,
CC and of the AKT1 signaling pathway. Phosphorylates SHC1. Mediates
CC phosphorylation of PIK3R1, the regulatory subunit of
CC phosphatidylinositol 3-kinase. Promotes phosphorylation of MAPK8 at
CC 'Thr-183' and 'Tyr-185', and of AKT1 at 'Ser-473'.
CC {ECO:0000269|PubMed:11532940, ECO:0000269|PubMed:15102829,
CC ECO:0000269|PubMed:15474514, ECO:0000269|PubMed:16076871,
CC ECO:0000269|PubMed:16452200, ECO:0000269|PubMed:17210781,
CC ECO:0000269|PubMed:19610651, ECO:0000269|PubMed:19779139,
CC ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20431062,
CC ECO:0000269|PubMed:20445537, ECO:0000269|PubMed:21273538,
CC ECO:0000269|PubMed:7675451, ECO:0000269|PubMed:8700872,
CC ECO:0000269|PubMed:9435229}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028,
CC ECO:0000269|PubMed:12881528, ECO:0000269|PubMed:7898938};
CC -!- ACTIVITY REGULATION: Present in an inactive conformation in the absence
CC of bound ligand. Binding of VEGFC or VEGFD leads to dimerization and
CC activation by autophosphorylation on tyrosine residues. Inhibited by
CC MAZ51. {ECO:0000269|PubMed:15102829, ECO:0000269|PubMed:19779139,
CC ECO:0000269|PubMed:20431062}.
CC -!- SUBUNIT: Interacts with VEGFC and VEGFD. Monomer in the absence of
CC bound VEGFC or VEGFD. Homodimer in the presence of bound VEGFC or
CC VEGFD. Can also form a heterodimer with KDR. Interacts with PTPN14; the
CC interaction is enhanced by stimulation with VEGFC. Interacts with CRK,
CC GRB2, PTK2/FAK1, SHC1, PIK3R1 and PTPN11/SHP-2. Identified in a complex
CC with SRC and ITGB1. {ECO:0000269|PubMed:12881528,
CC ECO:0000269|PubMed:15102829, ECO:0000269|PubMed:15474514,
CC ECO:0000269|PubMed:16076871, ECO:0000269|PubMed:16452200,
CC ECO:0000269|PubMed:18593464, ECO:0000269|PubMed:19610651,
CC ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:20431062,
CC ECO:0000269|PubMed:20826270, ECO:0000269|PubMed:23878260,
CC ECO:0000269|PubMed:7675451, ECO:0000269|PubMed:8700872,
CC ECO:0000269|PubMed:9435229}.
CC -!- INTERACTION:
CC P35916; P08238: HSP90AB1; NbExp=2; IntAct=EBI-1005467, EBI-352572;
CC P35916; P35968: KDR; NbExp=5; IntAct=EBI-1005467, EBI-1005487;
CC P35916; P49767: VEGFC; NbExp=2; IntAct=EBI-1005467, EBI-3405539;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20445537,
CC ECO:0000269|PubMed:7898938}; Single-pass type I membrane protein.
CC Cytoplasm {ECO:0000269|PubMed:16452200, ECO:0000269|PubMed:20445537}.
CC Nucleus {ECO:0000269|PubMed:16452200}. Note=Ligand-mediated
CC autophosphorylation leads to rapid internalization.
CC {ECO:0000269|PubMed:20445537}.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane; Single-pass type I
CC membrane protein. Note=Ligand-mediated autophosphorylation leads to
CC rapid internalization.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cell membrane; Single-pass type I
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Secreted. Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=Long;
CC IsoId=P35916-2; Sequence=Displayed;
CC Name=2; Synonyms=Short;
CC IsoId=P35916-1; Sequence=VSP_041995;
CC Name=3; Synonyms=sVegfr3;
CC IsoId=P35916-3; Sequence=VSP_041993, VSP_041994;
CC -!- TISSUE SPECIFICITY: Detected in endothelial cells (at protein level).
CC Widely expressed. Detected in fetal spleen, lung and brain. Detected in
CC adult liver, muscle, thymus, placenta, lung, testis, ovary, prostate,
CC heart, and kidney. {ECO:0000269|PubMed:1327515,
CC ECO:0000269|PubMed:20224550, ECO:0000269|PubMed:7675451}.
CC -!- DOMAIN: The first and second Ig-like C2-type (immunoglobulin-like)
CC domains are sufficient for VEGFC binding (PubMed:23878260). The fourth
CC and fifth Ig-like C2-type domains are sufficient for homodimerization
CC (PubMed:23878260). The fifth and seventh Ig-like C2-type domains are
CC required for autophosphorylation and further activation
CC (PubMed:23878260). {ECO:0000269|PubMed:23878260}.
CC -!- PTM: Autophosphorylated on tyrosine residues upon ligand binding.
CC Autophosphorylation occurs in trans, i.e. one subunit of the dimeric
CC receptor phosphorylates tyrosine residues on the other subunit.
CC Phosphorylation in response to H(2)O(2) is mediated by a process that
CC requires SRC and PRKCD activity. Phosphorylation at Tyr-1068 is
CC required for autophosphorylation at additional tyrosine residues.
CC Phosphorylation at Tyr-1063 and Tyr-1337 is important for interaction
CC with CRK and subsequent activation of MAPK8. Phosphorylation at Tyr-
CC 1230, Tyr-1231 and Tyr-1337 is important for interaction with GRB2 and
CC subsequent activation of the AKT1 and MAPK1/ERK2 and/or MAPK3/ERK1
CC signaling pathways. In response to endothelial cell adhesion onto
CC collagen, can also be phosphorylated in the absence of FLT4 kinase
CC activity by SRC at Tyr-830, Tyr-833, Tyr-853, Tyr-1063, Tyr-1333, and
CC Tyr-1337. {ECO:0000269|PubMed:12881528, ECO:0000269|PubMed:15102829,
CC ECO:0000269|PubMed:15474514, ECO:0000269|PubMed:16076871,
CC ECO:0000269|PubMed:20431062, ECO:0000269|PubMed:23878260,
CC ECO:0000269|PubMed:8700872}.
CC -!- DISEASE: Lymphatic malformation 1 (LMPHM1) [MIM:153100]: A form of
CC primary lymphedema, a disease characterized by swelling of body parts
CC due to developmental anomalies and functional defects of the lymphatic
CC system. Patients with lymphedema may suffer from recurrent local
CC infections. LMPHM1 is an autosomal dominant form with variable
CC expression and severity. Onset is usually at birth or in early
CC childhood but can occur later. Affected individuals manifest
CC lymphedema, predominantly in the lower limbs, and hypoplasia of
CC lymphatic vessels. Additional features are hemangioma and nail
CC dysplasia or papillomatosis. {ECO:0000269|PubMed:10835628,
CC ECO:0000269|PubMed:10856194, ECO:0000269|PubMed:12881528,
CC ECO:0000269|PubMed:15102829, ECO:0000269|PubMed:16924388,
CC ECO:0000269|PubMed:16965327, ECO:0000269|PubMed:17458866,
CC ECO:0000269|PubMed:19289394, ECO:0000269|PubMed:26091405,
CC ECO:0000269|PubMed:9817924}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hemangioma, capillary infantile (HCI) [MIM:602089]: A
CC condition characterized by dull red, firm, dome-shaped hemangiomas,
CC sharply demarcated from surrounding skin, usually presenting at birth
CC or occurring within the first two or three months of life. They result
CC from highly proliferative, localized growth of capillary endothelium
CC and generally undergo regression and involution without scarring.
CC {ECO:0000269|PubMed:11807987}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- DISEASE: Note=Plays an important role in tumor lymphangiogenesis, in
CC cancer cell survival, migration, and formation of metastases.
CC -!- DISEASE: Congenital heart defects, multiple types, 7 (CHTD7)
CC [MIM:618780]: An autosomal dominant disorder with incomplete penetrance
CC characterized by congenital developmental abnormalities involving
CC structures of the heart. Common defects include tetralogy of Fallot,
CC pulmonary stenosis or atresia, absent pulmonary valve, right aortic
CC arch, double aortic arch, and major aortopulmonary collateral arteries.
CC {ECO:0000269|PubMed:28991257, ECO:0000269|PubMed:30232381}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. CSF-1/PDGF receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA48290.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Wikipedia; Note=FLT4 entry;
CC URL="https://en.wikipedia.org/wiki/FLT4";
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DR EMBL; X69878; CAA49505.1; -; mRNA.
DR EMBL; U43143; AAA85215.1; -; mRNA.
DR EMBL; EU826564; ACF47600.1; -; mRNA.
DR EMBL; AY233382; AAO89504.1; -; mRNA.
DR EMBL; AY233383; AAO89505.1; -; mRNA.
DR EMBL; AK291679; BAF84368.1; -; mRNA.
DR EMBL; AC122714; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; X68203; CAA48290.1; ALT_INIT; mRNA.
DR EMBL; S66407; AAB28539.1; -; mRNA.
DR CCDS; CCDS43412.1; -. [P35916-1]
DR CCDS; CCDS4457.1; -. [P35916-2]
DR PIR; A48999; A48999.
DR RefSeq; NP_002011.2; NM_002020.4. [P35916-1]
DR RefSeq; NP_891555.2; NM_182925.4. [P35916-2]
DR PDB; 4BSJ; X-ray; 2.50 A; A=330-553.
DR PDB; 4BSK; X-ray; 4.20 A; A=23-229.
DR PDBsum; 4BSJ; -.
DR PDBsum; 4BSK; -.
DR AlphaFoldDB; P35916; -.
DR SMR; P35916; -.
DR BioGRID; 108612; 35.
DR CORUM; P35916; -.
DR DIP; DIP-5739N; -.
DR IntAct; P35916; 19.
DR MINT; P35916; -.
DR STRING; 9606.ENSP00000261937; -.
DR BindingDB; P35916; -.
DR ChEMBL; CHEMBL1955; -.
DR DrugBank; DB06626; Axitinib.
DR DrugBank; DB05932; Denibulin.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB06101; IMC-1C11.
DR DrugBank; DB09078; Lenvatinib.
DR DrugBank; DB06080; Linifanib.
DR DrugBank; DB09079; Nintedanib.
DR DrugBank; DB06589; Pazopanib.
DR DrugBank; DB08896; Regorafenib.
DR DrugBank; DB15685; Selpercatinib.
DR DrugBank; DB00398; Sorafenib.
DR DrugBank; DB01268; Sunitinib.
DR DrugBank; DB05075; TG-100801.
DR DrugBank; DB11800; Tivozanib.
DR DrugBank; DB04879; Vatalanib.
DR DrugCentral; P35916; -.
DR GuidetoPHARMACOLOGY; 1814; -.
DR GlyGen; P35916; 12 sites.
DR iPTMnet; P35916; -.
DR PhosphoSitePlus; P35916; -.
DR BioMuta; FLT4; -.
DR DMDM; 357529070; -.
DR jPOST; P35916; -.
DR MassIVE; P35916; -.
DR PaxDb; P35916; -.
DR PeptideAtlas; P35916; -.
DR PRIDE; P35916; -.
DR ProteomicsDB; 55166; -. [P35916-2]
DR ProteomicsDB; 55167; -. [P35916-1]
DR ProteomicsDB; 55168; -. [P35916-3]
DR Antibodypedia; 3429; 1073 antibodies from 45 providers.
DR DNASU; 2324; -.
DR Ensembl; ENST00000261937.11; ENSP00000261937.6; ENSG00000037280.16. [P35916-2]
DR Ensembl; ENST00000393347.7; ENSP00000377016.3; ENSG00000037280.16. [P35916-1]
DR GeneID; 2324; -.
DR KEGG; hsa:2324; -.
DR MANE-Select; ENST00000261937.11; ENSP00000261937.6; NM_182925.5; NP_891555.2.
DR UCSC; uc003mlz.4; human. [P35916-2]
DR CTD; 2324; -.
DR DisGeNET; 2324; -.
DR GeneCards; FLT4; -.
DR GeneReviews; FLT4; -.
DR HGNC; HGNC:3767; FLT4.
DR HPA; ENSG00000037280; Low tissue specificity.
DR MalaCards; FLT4; -.
DR MIM; 136352; gene.
DR MIM; 153100; phenotype.
DR MIM; 602089; phenotype.
DR MIM; 618780; phenotype.
DR neXtProt; NX_P35916; -.
DR OpenTargets; ENSG00000037280; -.
DR Orphanet; 79452; Milroy disease.
DR Orphanet; 464293; NON RARE IN EUROPE: Infantile capillary hemangioma.
DR Orphanet; 3303; Tetralogy of Fallot.
DR PharmGKB; PA28183; -.
DR VEuPathDB; HostDB:ENSG00000037280; -.
DR eggNOG; KOG0200; Eukaryota.
DR GeneTree; ENSGT00940000159358; -.
DR HOGENOM; CLU_000288_49_4_1; -.
DR InParanoid; P35916; -.
DR OMA; HIMQSCW; -.
DR OrthoDB; 236292at2759; -.
DR PhylomeDB; P35916; -.
DR TreeFam; TF325768; -.
DR BRENDA; 2.7.10.1; 2681.
DR PathwayCommons; P35916; -.
DR Reactome; R-HSA-195399; VEGF binds to VEGFR leading to receptor dimerization.
DR Reactome; R-HSA-9013695; NOTCH4 Intracellular Domain Regulates Transcription.
DR SignaLink; P35916; -.
DR SIGNOR; P35916; -.
DR BioGRID-ORCS; 2324; 12 hits in 1105 CRISPR screens.
DR ChiTaRS; FLT4; human.
DR GeneWiki; FLT4; -.
DR GenomeRNAi; 2324; -.
DR Pharos; P35916; Tclin.
DR PRO; PR:P35916; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; P35916; protein.
DR Bgee; ENSG00000037280; Expressed in right lobe of thyroid gland and 102 other tissues.
DR ExpressionAtlas; P35916; baseline and differential.
DR Genevisible; P35916; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0043235; C:receptor complex; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0019838; F:growth factor binding; IPI:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0019903; F:protein phosphatase binding; IPI:UniProtKB.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IMP:UniProtKB.
DR GO; GO:0005021; F:vascular endothelial growth factor receptor activity; IDA:UniProtKB.
DR GO; GO:0048514; P:blood vessel morphogenesis; ISS:UniProtKB.
DR GO; GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; IDA:UniProtKB.
DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IBA:GO_Central.
DR GO; GO:0048286; P:lung alveolus development; IEA:Ensembl.
DR GO; GO:0001945; P:lymph vessel development; ISS:BHF-UCL.
DR GO; GO:0001946; P:lymphangiogenesis; IMP:UniProtKB.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:UniProtKB.
DR GO; GO:0010595; P:positive regulation of endothelial cell migration; IMP:UniProtKB.
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:0046330; P:positive regulation of JNK cascade; IMP:UniProtKB.
DR GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IMP:UniProtKB.
DR GO; GO:0090037; P:positive regulation of protein kinase C signaling; IMP:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; IMP:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0060312; P:regulation of blood vessel remodeling; ISS:UniProtKB.
DR GO; GO:0003016; P:respiratory system process; IEA:Ensembl.
DR GO; GO:0002040; P:sprouting angiogenesis; ISS:UniProtKB.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR GO; GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; IDA:MGI.
DR GO; GO:0038084; P:vascular endothelial growth factor signaling pathway; IDA:UniProtKB.
DR GO; GO:0001944; P:vasculature development; ISS:UniProtKB.
DR DisProt; DP02600; -.
DR Gene3D; 2.60.40.10; -; 7.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR001824; Tyr_kinase_rcpt_3_CS.
DR InterPro; IPR041348; VEGFR-2_TMD.
DR InterPro; IPR009137; VEGFR3_rcpt.
DR PANTHER; PTHR24416:SF562; PTHR24416:SF562; 1.
DR Pfam; PF07679; I-set; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF17988; VEGFR-2_TMD; 1.
DR SMART; SM00409; IG; 6.
DR SMART; SM00408; IGc2; 4.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF48726; SSF48726; 6.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50835; IG_LIKE; 6.
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; Cytoplasm; Direct protein sequencing; Disease variant;
KW Disulfide bond; Glycoprotein; Immunoglobulin domain; Kinase; Membrane;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Receptor; Reference proteome;
KW Repeat; Secreted; Signal; Transferase; Transmembrane; Transmembrane helix;
KW Tyrosine-protein kinase.
FT SIGNAL 1..24
FT /evidence="ECO:0000269|PubMed:15340161"
FT CHAIN 25..1363
FT /note="Vascular endothelial growth factor receptor 3"
FT /id="PRO_0000016776"
FT TOPO_DOM 25..775
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 776..796
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 797..1363
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 30..127
FT /note="Ig-like C2-type 1"
FT DOMAIN 151..213
FT /note="Ig-like C2-type 2"
FT DOMAIN 219..326
FT /note="Ig-like C2-type 3"
FT DOMAIN 331..415
FT /note="Ig-like C2-type 4"
FT DOMAIN 422..552
FT /note="Ig-like C2-type 5"
FT DOMAIN 555..671
FT /note="Ig-like C2-type 6"
FT DOMAIN 678..764
FT /note="Ig-like C2-type 7"
FT DOMAIN 845..1173
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1291..1331
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 1037
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 851..859
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 879
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT MOD_RES 830
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000269|PubMed:20431062"
FT MOD_RES 833
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000269|PubMed:20431062"
FT MOD_RES 853
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000269|PubMed:20431062"
FT MOD_RES 1063
FT /note="Phosphotyrosine; by autocatalysis and SRC"
FT /evidence="ECO:0000269|PubMed:16076871,
FT ECO:0000269|PubMed:20431062"
FT MOD_RES 1068
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:16076871,
FT ECO:0000269|PubMed:20431062"
FT MOD_RES 1230
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:12881528,
FT ECO:0000269|PubMed:16076871"
FT MOD_RES 1231
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:12881528,
FT ECO:0000269|PubMed:16076871"
FT MOD_RES 1265
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:12881528"
FT MOD_RES 1333
FT /note="Phosphotyrosine; by autocatalysis and SRC"
FT /evidence="ECO:0000269|PubMed:12881528,
FT ECO:0000269|PubMed:20431062"
FT MOD_RES 1337
FT /note="Phosphotyrosine; by autocatalysis and SRC"
FT /evidence="ECO:0000269|PubMed:12881528,
FT ECO:0000269|PubMed:16076871, ECO:0000269|PubMed:20431062"
FT MOD_RES 1363
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:12881528"
FT CARBOHYD 33
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:23878260,
FT ECO:0007744|PDB:4BSK"
FT CARBOHYD 104
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:23878260,
FT ECO:0007744|PDB:4BSK"
FT CARBOHYD 166
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 251
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 299
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 411
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:23878260,
FT ECO:0007744|PDB:4BSK"
FT CARBOHYD 515
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:23878260,
FT ECO:0007744|PDB:4BSK"
FT CARBOHYD 527
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952"
FT CARBOHYD 594
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 683
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 690
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 758
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 51..111
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:23878260"
FT DISULFID 158..206
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:23878260"
FT DISULFID 252..310
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 445..534
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:23878260"
FT DISULFID 466..486
FT /evidence="ECO:0000269|PubMed:23878260"
FT DISULFID 578..653
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 699..751
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT VAR_SEQ 724..765
FT /note="VDLADSNQKLSIQRVREEDAGRYLCSVCNAKGCVNSSASVAV -> REGGPG
FT EGQVRRPARPTIPNPGGPAPPPHPLQESTWRTPTRS (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:18593464"
FT /id="VSP_041993"
FT VAR_SEQ 766..1298
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:18593464"
FT /id="VSP_041994"
FT VAR_SEQ 1298..1363
FT /note="SCKGPGQNVAVTRAHPDSQGRRRRPERGARGGQVFYNSEYGELSEPSEEDHC
FT SPSARVTFFTDNSY -> R (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:1319394,
FT ECO:0000303|PubMed:1327515, ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:8386825, ECO:0000303|PubMed:8700872,
FT ECO:0000303|Ref.7"
FT /id="VSP_041995"
FT VARIANT 82..1363
FT /note="Missing (in CHTD7)"
FT /evidence="ECO:0000269|PubMed:28991257"
FT /id="VAR_083806"
FT VARIANT 149
FT /note="N -> D (in dbSNP:rs34221241)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042062"
FT VARIANT 361..1363
FT /note="Missing (in CHTD7)"
FT /evidence="ECO:0000269|PubMed:28991257"
FT /id="VAR_083807"
FT VARIANT 378
FT /note="R -> C (in a renal clear cell carcinoma sample;
FT somatic mutation; dbSNP:rs372947534)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042063"
FT VARIANT 494
FT /note="T -> A (in dbSNP:rs307826)"
FT /evidence="ECO:0000269|PubMed:11807987,
FT ECO:0000269|PubMed:17344846"
FT /id="VAR_018407"
FT VARIANT 527
FT /note="N -> S (in dbSNP:rs35874891)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_034379"
FT VARIANT 641
FT /note="P -> S (in dbSNP:rs55667289)"
FT /evidence="ECO:0000269|PubMed:10835628,
FT ECO:0000269|PubMed:17344846"
FT /id="VAR_018408"
FT VARIANT 736..1363
FT /note="Missing (in CHTD7)"
FT /evidence="ECO:0000269|PubMed:28991257"
FT /id="VAR_083808"
FT VARIANT 741
FT /note="Missing (in CHTD7; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30232381"
FT /id="VAR_083809"
FT VARIANT 833..1363
FT /note="Missing (in CHTD7)"
FT /evidence="ECO:0000269|PubMed:30232381"
FT /id="VAR_083810"
FT VARIANT 855
FT /note="A -> T (in LMPHM1; recessive form; results in
FT reduced autophosphorylation; results in impaired ligand-
FT induced receptor internalization and downstream signaling;
FT dbSNP:rs121909657)"
FT /evidence="ECO:0000269|PubMed:19289394"
FT /id="VAR_074044"
FT VARIANT 857
FT /note="G -> R (in LMPHM1; loss of kinase activity;
FT dbSNP:rs267606818)"
FT /evidence="ECO:0000269|PubMed:10835628,
FT ECO:0000269|PubMed:15102829"
FT /id="VAR_018409"
FT VARIANT 868
FT /note="H -> Y (in dbSNP:rs35171798)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042064"
FT VARIANT 878
FT /note="V -> M (in LMPHM1; dbSNP:rs121909654)"
FT /evidence="ECO:0000269|PubMed:16965327"
FT /id="VAR_074045"
FT VARIANT 890
FT /note="H -> Q (in dbSNP:rs448012)"
FT /evidence="ECO:0000269|PubMed:11807987,
FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:8386825,
FT ECO:0000269|Ref.7"
FT /id="VAR_018410"
FT VARIANT 954
FT /note="P -> S (in HCI; dbSNP:rs34255532)"
FT /evidence="ECO:0000269|PubMed:11807987"
FT /id="VAR_018411"
FT VARIANT 999..1363
FT /note="Missing (in CHTD7)"
FT /evidence="ECO:0000269|PubMed:28991257"
FT /id="VAR_083811"
FT VARIANT 1010
FT /note="T -> I (in a metastatic melanoma sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042065"
FT VARIANT 1020
FT /note="Q -> L (in LMPHM1)"
FT /evidence="ECO:0000269|PubMed:17458866"
FT /id="VAR_074046"
FT VARIANT 1031
FT /note="R -> Q (in dbSNP:rs56082504)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042066"
FT VARIANT 1035
FT /note="H -> Q (probable disease-associated variant found in
FT sporadic congenital lymphedema; de novo mutation)"
FT /evidence="ECO:0000269|PubMed:16965327"
FT /id="VAR_074047"
FT VARIANT 1035
FT /note="H -> R (in LMPHM1; loss of kinase activity;
FT dbSNP:rs121909653)"
FT /evidence="ECO:0000269|PubMed:10856194"
FT /id="VAR_018412"
FT VARIANT 1041
FT /note="R -> P (in LMPHM1; loss of kinase activity;
FT dbSNP:rs121909650)"
FT /evidence="ECO:0000269|PubMed:10835628,
FT ECO:0000269|PubMed:12881528"
FT /id="VAR_018413"
FT VARIANT 1044
FT /note="L -> P (in LMPHM1; loss of kinase activity;
FT dbSNP:rs121909651)"
FT /evidence="ECO:0000269|PubMed:10835628"
FT /id="VAR_018414"
FT VARIANT 1049
FT /note="D -> N (in dbSNP:rs56310180)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042067"
FT VARIANT 1075
FT /note="R -> Q (in dbSNP:rs1400220848)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042068"
FT VARIANT 1086
FT /note="I -> T (in LMPHM1; dbSNP:rs121909655)"
FT /evidence="ECO:0000269|PubMed:16965327"
FT /id="VAR_074048"
FT VARIANT 1106
FT /note="E -> K (in LMPHM1; dbSNP:rs121909656)"
FT /evidence="ECO:0000269|PubMed:16924388"
FT /id="VAR_074049"
FT VARIANT 1108
FT /note="Missing (in LMPHM1)"
FT /evidence="ECO:0000269|PubMed:16965327"
FT /id="VAR_074050"
FT VARIANT 1114
FT /note="P -> L (in LMPHM1; loss of kinase activity;
FT dbSNP:rs121909652)"
FT /evidence="ECO:0000269|PubMed:10835628,
FT ECO:0000269|PubMed:9817924"
FT /id="VAR_018415"
FT VARIANT 1137
FT /note="P -> S (in HCI)"
FT /evidence="ECO:0000269|PubMed:11807987"
FT /id="VAR_018416"
FT VARIANT 1146
FT /note="R -> H (in dbSNP:rs1130379)"
FT /evidence="ECO:0000269|PubMed:11807987,
FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:8386825,
FT ECO:0000269|Ref.7"
FT /id="VAR_018417"
FT VARIANT 1173
FT /note="L -> V (in CHTD7; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30232381"
FT /id="VAR_083812"
FT VARIANT 1192..1363
FT /note="Missing (in CHTD7)"
FT /evidence="ECO:0000269|PubMed:30232381"
FT /id="VAR_083813"
FT VARIANT 1235
FT /note="S -> C (in LMPHM1; recessive form)"
FT /evidence="ECO:0000269|PubMed:26091405"
FT /id="VAR_074051"
FT MUTAGEN 446
FT /note="T->E: Decreases autophosphorylation on tyrosine
FT residues upon ligand binding; when associated with A-516.
FT Abolishes autophosphorylation on tyrosine residues upon
FT ligand binding; when associated with A-516 and A-737."
FT /evidence="ECO:0000269|PubMed:23878260"
FT MUTAGEN 516
FT /note="K->A: Decreases autophosphorylation on tyrosine
FT residues upon ligand binding; when associated with E-446.
FT Abolishes autophosphorylation on tyrosine residues upon
FT ligand binding; when associated with E-446 and A-737."
FT /evidence="ECO:0000269|PubMed:23878260"
FT MUTAGEN 737
FT /note="R->A: Decreases autophosphorylation on tyrosine
FT residues upon ligand binding. Abolishes autophosphorylation
FT on tyrosine residues upon ligand binding; when associated
FT with E-446 and A-516."
FT /evidence="ECO:0000269|PubMed:23878260"
FT MUTAGEN 879
FT /note="K->G: Abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:12881528"
FT MUTAGEN 1063
FT /note="Y->F: Loss of phosphorylation site. No effect on
FT stimulation of cell proliferation and cell migration."
FT /evidence="ECO:0000269|PubMed:16076871,
FT ECO:0000269|PubMed:20431062"
FT MUTAGEN 1068
FT /note="Y->F: Global loss of autophosphorylation. Abolishes
FT stimulation of cell proliferation and cell migration."
FT /evidence="ECO:0000269|PubMed:16076871,
FT ECO:0000269|PubMed:20431062"
FT MUTAGEN 1230
FT /note="Y->F: Loss of phosphorylation site. Strongly reduces
FT stimulation of cell proliferation and cell migration."
FT /evidence="ECO:0000269|PubMed:12881528,
FT ECO:0000269|PubMed:16076871"
FT MUTAGEN 1231
FT /note="Y->F: Loss of phosphorylation site. Strongly reduces
FT stimulation of cell proliferation and cell migration."
FT /evidence="ECO:0000269|PubMed:12881528,
FT ECO:0000269|PubMed:16076871"
FT MUTAGEN 1265
FT /note="Y->F: Loss of phosphorylation site. No effect on
FT stimulation of cell proliferation and cell migration."
FT /evidence="ECO:0000269|PubMed:12881528"
FT MUTAGEN 1333
FT /note="Y->F: Loss of phosphorylation site. Reduced
FT autophosphorylation."
FT /evidence="ECO:0000269|PubMed:12881528,
FT ECO:0000269|PubMed:7675451"
FT MUTAGEN 1337
FT /note="Y->F: Reduced autophosphorylation. Strongly reduces
FT stimulation of cell proliferation and cell migration."
FT /evidence="ECO:0000269|PubMed:12881528,
FT ECO:0000269|PubMed:20431062, ECO:0000269|PubMed:7675451"
FT MUTAGEN 1363
FT /note="Y->F: Loss of phosphorylation site. Slightly reduced
FT autophosphorylation."
FT /evidence="ECO:0000269|PubMed:12881528,
FT ECO:0000269|PubMed:7675451"
FT CONFLICT 24
FT /note="G -> D (in Ref. 3; CAA49505 and 7; AAO89504/
FT AAO89505)"
FT /evidence="ECO:0000305"
FT CONFLICT 538
FT /note="N -> D (in Ref. 8; BAF84368)"
FT /evidence="ECO:0000305"
FT CONFLICT 745
FT /note="R -> P (in Ref. 3; CAA49505 and 7; AAO89504/
FT AAO89505)"
FT /evidence="ECO:0000305"
FT CONFLICT 752..753
FT /note="NA -> RP (in Ref. 3; CAA49505 and 7; AAO89504/
FT AAO89505)"
FT /evidence="ECO:0000305"
FT CONFLICT 1128
FT /note="L -> V (in Ref. 3; CAA49505 and 7; AAO89504/
FT AAO89505)"
FT /evidence="ECO:0000305"
FT CONFLICT 1164
FT /note="E -> D (in Ref. 3; CAA49505)"
FT /evidence="ECO:0000305"
FT STRAND 332..339
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 341..346
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 350..362
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 365..370
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 381..388
FT /evidence="ECO:0007829|PDB:4BSJ"
FT HELIX 391..393
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 395..403
FT /evidence="ECO:0007829|PDB:4BSJ"
FT TURN 404..407
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 408..424
FT /evidence="ECO:0007829|PDB:4BSJ"
FT HELIX 425..428
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 441..451
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 457..464
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 501..511
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 514..524
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 530..538
FT /evidence="ECO:0007829|PDB:4BSJ"
FT STRAND 541..549
FT /evidence="ECO:0007829|PDB:4BSJ"
SQ SEQUENCE 1363 AA; 152757 MW; B1473AAAC95E7E93 CRC64;
MQRGAALCLR LWLCLGLLDG LVSGYSMTPP TLNITEESHV IDTGDSLSIS CRGQHPLEWA
WPGAQEAPAT GDKDSEDTGV VRDCEGTDAR PYCKVLLLHE VHANDTGSYV CYYKYIKARI
EGTTAASSYV FVRDFEQPFI NKPDTLLVNR KDAMWVPCLV SIPGLNVTLR SQSSVLWPDG
QEVVWDDRRG MLVSTPLLHD ALYLQCETTW GDQDFLSNPF LVHITGNELY DIQLLPRKSL
ELLVGEKLVL NCTVWAEFNS GVTFDWDYPG KQAERGKWVP ERRSQQTHTE LSSILTIHNV
SQHDLGSYVC KANNGIQRFR ESTEVIVHEN PFISVEWLKG PILEATAGDE LVKLPVKLAA
YPPPEFQWYK DGKALSGRHS PHALVLKEVT EASTGTYTLA LWNSAAGLRR NISLELVVNV
PPQIHEKEAS SPSIYSRHSR QALTCTAYGV PLPLSIQWHW RPWTPCKMFA QRSLRRRQQQ
DLMPQCRDWR AVTTQDAVNP IESLDTWTEF VEGKNKTVSK LVIQNANVSA MYKCVVSNKV
GQDERLIYFY VTTIPDGFTI ESKPSEELLE GQPVLLSCQA DSYKYEHLRW YRLNLSTLHD
AHGNPLLLDC KNVHLFATPL AASLEEVAPG ARHATLSLSI PRVAPEHEGH YVCEVQDRRS
HDKHCHKKYL SVQALEAPRL TQNLTDLLVN VSDSLEMQCL VAGAHAPSIV WYKDERLLEE
KSGVDLADSN QKLSIQRVRE EDAGRYLCSV CNAKGCVNSS ASVAVEGSED KGSMEIVILV
GTGVIAVFFW VLLLLIFCNM RRPAHADIKT GYLSIIMDPG EVPLEEQCEY LSYDASQWEF
PRERLHLGRV LGYGAFGKVV EASAFGIHKG SSCDTVAVKM LKEGATASEH RALMSELKIL
IHIGNHLNVV NLLGACTKPQ GPLMVIVEFC KYGNLSNFLR AKRDAFSPCA EKSPEQRGRF
RAMVELARLD RRRPGSSDRV LFARFSKTEG GARRASPDQE AEDLWLSPLT MEDLVCYSFQ
VARGMEFLAS RKCIHRDLAA RNILLSESDV VKICDFGLAR DIYKDPDYVR KGSARLPLKW
MAPESIFDKV YTTQSDVWSF GVLLWEIFSL GASPYPGVQI NEEFCQRLRD GTRMRAPELA
TPAIRRIMLN CWSGDPKARP AFSELVEILG DLLQGRGLQE EEEVCMAPRS SQSSEEGSFS
QVSTMALHIA QADAEDSPPS LQRHSLAARY YNWVSFPGCL ARGAETRGSS RMKTFEEFPM
TPTTYKGSVD NQTDSGMVLA SEEFEQIESR HRQESGFSCK GPGQNVAVTR AHPDSQGRRR
RPERGARGGQ VFYNSEYGEL SEPSEEDHCS PSARVTFFTD NSY
