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 24-JAN-2024, entry version 233. 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=3; 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"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; 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; 250. DR CORUM; P35916; -. DR DIP; DIP-5739N; -. DR IntAct; P35916; 232. 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 TCDB; 8.A.23.1.43; the basigin (basigin) family. DR GlyCosmos; P35916; 12 sites, No reported glycans. 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; 9606-ENSP00000261937; -. DR PeptideAtlas; P35916; -. DR ProteomicsDB; 55166; -. [P35916-2] DR ProteomicsDB; 55167; -. [P35916-1] DR ProteomicsDB; 55168; -. [P35916-3] DR Antibodypedia; 3429; 1180 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 AGR; HGNC:3767; -. 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; WDDRQGM; -. DR OrthoDB; 1614410at2759; -. 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 1191 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 104 other cell types or tissues. DR ExpressionAtlas; P35916; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. 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:0001525; P:angiogenesis; IBA:GO_Central. 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: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:0030335; P:positive regulation of cell migration; IBA:GO_Central. 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: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:0043408; P:regulation of MAPK cascade; IBA:GO_Central. 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; TAS:ProtInc. 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 CDD; cd00096; Ig; 1. DR CDD; cd05862; IgI_VEGFR; 1. DR CDD; cd05863; IgI_VEGFR-3; 1. DR CDD; cd05102; PTKc_VEGFR3; 1. DR DisProt; DP02600; -. DR Gene3D; 2.60.40.10; Immunoglobulins; 7. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. 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; IPR013151; Immunoglobulin. 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 PANTHER; PTHR24416; TYROSINE-PROTEIN KINASE RECEPTOR; 1. DR PANTHER; PTHR24416:SF49; VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 3; 1. DR Pfam; PF07679; I-set; 1. DR Pfam; PF00047; ig; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR Pfam; PF21339; VEGFR-1-like_Ig-like; 1. DR Pfam; PF17988; VEGFR-2_TMD; 1. DR PIRSF; PIRSF000615; TyrPK_CSF1-R; 1. DR PRINTS; PR01832; VEGFRECEPTOR. DR PRINTS; PR01835; VEGFRECEPTR3. DR SMART; SM00409; IG; 6. DR SMART; SM00408; IGc2; 4. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF48726; Immunoglobulin; 6. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 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. DR Genevisible; P35916; HS. 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; uncertain 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 FT ligand-induced receptor internalization and downstream FT signaling; 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 (found in sporadic congenital lymphedema; FT uncertain significance)" 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; uncertain 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; FT AAO89504/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; FT AAO89504/AAO89505)" FT /evidence="ECO:0000305" FT CONFLICT 752..753 FT /note="NA -> RP (in Ref. 3; CAA49505 and 7; FT AAO89504/AAO89505)" FT /evidence="ECO:0000305" FT CONFLICT 1128 FT /note="L -> V (in Ref. 3; CAA49505 and 7; FT AAO89504/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 //