ID FLT3_HUMAN Reviewed; 993 AA. AC P36888; A0AVG9; B7ZLT7; B7ZLT8; F5H0A0; Q13414; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 21-AUG-2007, sequence version 2. DT 28-JAN-2026, entry version 224. DE RecName: Full=Receptor-type tyrosine-protein kinase FLT3; DE EC=2.7.10.1; DE AltName: Full=FL cytokine receptor; DE AltName: Full=Fetal liver kinase-2; DE Short=FLK-2; DE AltName: Full=Fms-like tyrosine kinase 3; DE Short=FLT-3; DE AltName: Full=Stem cell tyrosine kinase 1; DE Short=STK-1; DE AltName: CD_antigen=CD135; DE Flags: Precursor; GN Name=FLT3; Synonyms=CD135, FLK2, STK1; 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 1), FUNCTION, AND TISSUE SPECIFICITY. RC TISSUE=Bone marrow; RX PubMed=7507245; DOI=10.1073/pnas.91.2.459; RA Small D., Levenstein M., Kim E., Carow C., Amin S., Rockwell P., Witte L., RA Burrow C., Ratajczak M.Z., Gewirtz A.M., Civin C.I.; RT "STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ RT human bone marrow cells and is involved in the proliferation of early RT progenitor/stem cells."; RL Proc. Natl. Acad. Sci. U.S.A. 91:459-463(1994). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT RP MET-227. RC TISSUE=Lymphocyte; RX PubMed=8394751; RA Rosnet O., Schiff C., Pebusque M.J., Marchetto S., Tonnelle C., Toiron Y., RA Birg F., Birnbaum D.; RT "Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic RT cells."; RL Blood 82:1110-1119(1993). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057823; DOI=10.1038/nature02379; RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., RA Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., RA Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L., RA Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., RA Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., RA Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., RA Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., RA Frankish A.G., Frankland J., French L., Garner P., Garnett J., RA Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., RA Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., RA Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., RA Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., RA Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., RA Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., RA Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., RA Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., RA Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., RA Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., RA Rogers J., Ross M.T.; RT "The DNA sequence and analysis of human chromosome 13."; RL Nature 428:522-528(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT MET-227. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP MET-227. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 783-942 (ISOFORM 1). RC TISSUE=Testis; RX PubMed=2004790; DOI=10.1016/0888-7543(91)90270-o; RA Rosnet O., Mattei M.-G., Marchetto S., Birnbaum D.; RT "Isolation and chromosomal localization of a novel FMS-like tyrosine kinase RT gene."; RL Genomics 9:380-385(1991). RN [7] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=8637232; RA Rosnet O., Buhring H.J., Marchetto S., Rappold I., Lavagna C., Sainty D., RA Arnoulet C., Chabannon C., Kanz L., Hannum C., Birnbaum D.; RT "Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of RT normal and malignant hematopoietic cells."; RL Leukemia 10:238-248(1996). RN [8] RP INVOLVEMENT IN AML. RX PubMed=8946930; RA Nakao M., Yokota S., Iwai T., Kaneko H., Horiike S., Kashima K., Sonoda Y., RA Fujimoto T., Misawa S.; RT "Internal tandem duplication of the flt3 gene found in acute myeloid RT leukemia."; RL Leukemia 10:1911-1918(1996). RN [9] RP INVOLVEMENT IN AML, SUBUNIT, PHOSPHORYLATION, AND MUTAGENESIS OF TYR-589 RP AND TYR-591. RX PubMed=9737679; DOI=10.1038/sj.leu.2401130; RA Kiyoi H., Towatari M., Yokota S., Hamaguchi M., Ohno R., Saito H., Naoe T.; RT "Internal tandem duplication of the FLT3 gene is a novel modality of RT elongation mutation which causes constitutive activation of the product."; RL Leukemia 12:1333-1337(1998). RN [10] RP FUNCTION IN PROMOTING PHOSPHORYLATION OF SHC1; PTPN6/SHP; PTPN11/SHP-2; RP MAPK1/ERK2; MAPK3/ERK1, AUTOPHOSPHORYLATION, AND INTERACTION WITH GRB2. RX PubMed=10080542; DOI=10.1002/jlb.65.3.372; RA Zhang S., Mantel C., Broxmeyer H.E.; RT "Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and RT their association with Grb2 and Shc in Baf3/Flt3 cells."; RL J. Leukoc. Biol. 65:372-380(1999). RN [11] RP FUNCTION IN ACTIVATION OF AKT1; MAPK1/ERK2; MAPK3/ERK1; STAT5A AND STAT5B, RP PHOSPHORYLATION, FUNCTION IN ACTIVATION OF THE RAS PATHWAY, AND INVOLVEMENT RP IN AML. RX PubMed=11090077; RA Mizuki M., Fenski R., Halfter H., Matsumura I., Schmidt R., Muller C., RA Gruning W., Kratz-Albers K., Serve S., Steur C., Buchner T., Kienast J., RA Kanakura Y., Berdel W.E., Serve H.; RT "Flt3 mutations from patients with acute myeloid leukemia induce RT transformation of 32D cells mediated by the Ras and STAT5 pathways."; RL Blood 96:3907-3914(2000). RN [12] RP FUNCTION IN ACTIVATION OF AKT1, AND INVOLVEMENT IN AML. RX PubMed=16266983; DOI=10.1158/0008-5472.can-05-0422; RA Brandts C.H., Sargin B., Rode M., Biermann C., Lindtner B., Schwable J., RA Buerger H., Muller-Tidow C., Choudhary C., McMahon M., Berdel W.E., RA Serve H.; RT "Constitutive activation of Akt by Flt3 internal tandem duplications is RT necessary for increased survival, proliferation, and myeloid RT transformation."; RL Cancer Res. 65:9643-9650(2005). RN [13] RP SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-591, RP DEPHOSPHORYLATION BY PTPN1; PTPN6/SHP-1 AND PTPN12, PROTEASOMAL RP DEGRADATION, GLYCOSYLATION, AND MUTAGENESIS OF LYS-644. RX PubMed=15831474; DOI=10.1128/mcb.25.9.3690-3703.2005; RA Schmidt-Arras D.E., Bohmer A., Markova B., Choudhary C., Serve H., RA Bohmer F.D.; RT "Tyrosine phosphorylation regulates maturation of receptor tyrosine RT kinases."; RL Mol. Cell. Biol. 25:3690-3703(2005). RN [14] RP FUNCTION IN ACTIVATION OF STAT5A AND/OR STAT5B, PHOSPHORYLATION AT TYR-591; RP TYR-726; TYR-842; TYR-955 AND TYR-969, IDENTIFICATION BY MASS SPECTROMETRY, RP AND MUTAGENESIS OF TYR-589 AND TYR-591. RX PubMed=16627759; DOI=10.1182/blood-2005-11-011429; RA Rocnik J.L., Okabe R., Yu J.C., Lee B.H., Giese N., Schenkein D.P., RA Gilliland D.G.; RT "Roles of tyrosine 589 and 591 in STAT5 activation and transformation RT mediated by FLT3-ITD."; RL Blood 108:1339-1345(2006). RN [15] RP INTERACTION WITH PTPN11/SHP2; LYN; FGR; HCK AND SRC, AUTOPHOSPHORYLATION, RP MUTAGENESIS OF TYR-589 AND TYR-599, AND PHOSPHORYLATION AT TYR-572; RP SER-574; TYR-589; TYR-591 AND TYR-599. RX PubMed=16684964; DOI=10.1182/blood-2005-07-008896; RA Heiss E., Masson K., Sundberg C., Pedersen M., Sun J., Bengtsson S., RA Ronnstrand L.; RT "Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as RT ligand-induced autophosphorylation sites involved in binding of Src family RT kinases and the protein tyrosine phosphatase SHP2."; RL Blood 108:1542-1550(2006). RN [16] RP REGION INVOLVED IN REGULATION OF KINASE ACTIVITY, AUTOREGULATORY DOMAIN, RP AND INVOLVEMENT IN AML. RX PubMed=18305215; DOI=10.1182/blood-2008-01-117770; RA Meshinchi S., Stirewalt D.L., Alonzo T.A., Boggon T.J., Gerbing R.B., RA Rocnik J.L., Lange B.J., Gilliland D.G., Radich J.P.; RT "Structural and numerical variation of FLT3/ITD in pediatric AML."; RL Blood 111:4930-4933(2008). RN [17] RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=18490735; DOI=10.4049/jimmunol.180.11.7358; RA Kikushige Y., Yoshimoto G., Miyamoto T., Iino T., Mori Y., Iwasaki H., RA Niiro H., Takenaka K., Nagafuji K., Harada M., Ishikawa F., Akashi K.; RT "Human Flt3 is expressed at the hematopoietic stem cell and the RT granulocyte/macrophage progenitor stages to maintain cell survival."; RL J. Immunol. 180:7358-7367(2008). RN [18] RP PHOSPHORYLATION AT TYR-589; TYR-591; TYR-599; TYR-726; TYR-768; TYR-793; RP TYR-842 AND TYR-955. RX PubMed=19477218; DOI=10.1016/j.exphem.2009.05.008; RA Razumovskaya E., Masson K., Khan R., Bengtsson S., Ronnstrand L.; RT "Oncogenic Flt3 receptors display different specificity and kinetics of RT autophosphorylation."; RL Exp. Hematol. 37:979-989(2009). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-759 AND SER-993, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [20] RP FUNCTION IN ACTIVATION OF FES AND FER, AND INTERACTION WITH FES AND FER. RX PubMed=20111072; DOI=10.1038/leu.2009.301; RA Voisset E., Lopez S., Chaix A., Georges C., Hanssens K., Prebet T., RA Dubreuil P., De Sepulveda P.; RT "FES kinases are required for oncogenic FLT3 signaling."; RL Leukemia 24:721-728(2010). RN [21] RP UBIQUITINATION. RX PubMed=20508617; DOI=10.1038/leu.2010.114; RA Buchwald M., Pietschmann K., Muller J.P., Bohmer F.D., Heinzel T., RA Kramer O.H.; RT "Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for RT proteasomal degradation."; RL Leukemia 24:1412-1421(2010). RN [22] RP FUNCTION. RX PubMed=21067588; DOI=10.1186/1476-4598-9-292; RA Chen W., Drakos E., Grammatikakis I., Schlette E.J., Li J., Leventaki V., RA Staikou-Drakopoulou E., Patsouris E., Panayiotidis P., Medeiros L.J., RA Rassidakis G.Z.; RT "mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3- RT mutated acute myeloid leukemia cells."; RL Mol. Cancer 9:292-292(2010). RN [23] RP INTERACTION WITH PTPRJ/DEP1, FUNCTION IN ACTIVATION OF MAPK1/ERK2; RP MAPK3/ERK1; PLCG1; STAT5A AND/OR STAT5B, GLYCOSYLATION, UBIQUITINATION, AND RP PHOSPHORYLATION AT TYR-572; TYR-589; TYR-591; TYR-599; TYR-768; TYR-793; RP TYR-842 AND TYR-955. RX PubMed=21262971; DOI=10.1074/jbc.m110.205021; RA Arora D., Stopp S., Bohmer S.A., Schons J., Godfrey R., Masson K., RA Razumovskaya E., Ronnstrand L., Tanzer S., Bauer R., Bohmer F.D., RA Muller J.P.; RT "Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 RT signaling."; RL J. Biol. Chem. 286:10918-10929(2011). RN [24] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=21516120; DOI=10.1038/onc.2011.110; RA Zheng R., Bailey E., Nguyen B., Yang X., Piloto O., Levis M., Small D.; RT "Further activation of FLT3 mutants by FLT3 ligand."; RL Oncogene 30:4004-4014(2011). RN [25] RP REVIEW. RX PubMed=12951584; DOI=10.1038/nrc1169; RA Stirewalt D.L., Radich J.P.; RT "The role of FLT3 in haematopoietic malignancies."; RL Nat. Rev. Cancer 3:650-665(2003). RN [26] RP REVIEW. RX PubMed=19549778; DOI=10.1158/1078-0432.ccr-08-1123; RA Meshinchi S., Appelbaum F.R.; RT "Structural and functional alterations of FLT3 in acute myeloid leukemia."; RL Clin. Cancer Res. 15:4263-4269(2009). RN [27] RP INTERACTION WITH HUMAN CYTOMEGALOVIRUS PROTEIN UL7. RX PubMed=29691342; DOI=10.1128/mbio.00682-18; RA Crawford L.B., Kim J.H., Collins-McMillen D., Lee B.J., Landais I., RA Held C., Nelson J.A., Yurochko A.D., Caposio P.; RT "Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for RT Hematopoietic Cell Differentiation and Viral Reactivation."; RL MBio 9:0-0(2018). RN [28] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 564-958, AND ACTIVITY REGULATION. RX PubMed=14759363; DOI=10.1016/s1097-2765(03)00505-7; RA Griffith J., Black J., Faerman C., Swenson L., Wynn M., Lu F., Lippke J., RA Saxena K.; RT "The structural basis for autoinhibition of FLT3 by the juxtamembrane RT domain."; RL Mol. Cell 13:169-178(2004). RN [29] RP X-RAY CRYSTALLOGRAPHY (4.3 ANGSTROMS) OF 27-436 IN COMPLEX WITH FLT3LG, RP SUBUNIT, INTERACTION WITH FLT3LG, GLYCOSYLATION AT ASN-43; ASN-100; RP ASN-151; ASN-306; ASN-323; ASN-351 AND ASN-354, IDENTIFICATION BY MASS RP SPECTROMETRY, AND DISULFIDE BONDS. RX PubMed=21389326; DOI=10.1182/blood-2011-01-329532; RA Verstraete K., Vandriessche G., Januar M., Elegheert J., Shkumatov A.V., RA Desfosses A., Van Craenenbroeck K., Svergun D.I., Gutsche I., Vergauwen B., RA Savvides S.N.; RT "Structural insights into the extracellular assembly of the hematopoietic RT Flt3 signaling complex."; RL Blood 118:60-68(2011). RN [30] RP VARIANTS TYR-835 DEL; HIS-835 AND TYR-835, AND INVOLVEMENT IN AML. RX PubMed=11442493; DOI=10.1046/j.1365-2141.2001.02850.x; RA Abu-Duhier F.M., Goodeve A.C., Wilson G.A., Care R.S., Peake I.R., RA Reilly J.T.; RT "Identification of novel FLT-3 Asp835 mutations in adult acute myeloid RT leukaemia."; RL Br. J. Haematol. 113:983-988(2001). RN [31] RP VARIANTS ASN-835; GLU-835; HIS-835; VAL-835 AND TYR-835, CHARACTERIZATION RP OF VARIANTS ASN-835; GLU-835; HIS-835; VAL-835 AND TYR-835, RP PHOSPHORYLATION, AND INVOLVEMENT IN AML. RX PubMed=11290608; DOI=10.1182/blood.v97.8.2434; RA Yamamoto Y., Kiyoi H., Nakano Y., Suzuki R., Kodera Y., Miyawaki S., RA Asou N., Kuriyama K., Yagasaki F., Shimazaki C., Akiyama H., Saito K., RA Nishimura M., Motoji T., Shinagawa K., Takeshita A., Saito H., Ueda R., RA Ohno R., Naoe T.; RT "Activating mutation of D835 within the activation loop of FLT3 in human RT hematologic malignancies."; RL Blood 97:2434-2439(2001). RN [32] RP VARIANTS GLU-835; HIS-835; TYR-835; ILE-836 DEL AND MET-836, FUNCTION IN RP ACTIVATION OF STAT5A AND/OR STAT5B, PHOSPHORYLATION, AND INVOLVEMENT IN RP AML. RX PubMed=14504097; DOI=10.1182/blood-2003-02-0418; RA Taketani T., Taki T., Sugita K., Furuichi Y., Ishii E., Hanada R., RA Tsuchida M., Sugita K., Ida K., Hayashi Y.; RT "FLT3 mutations in the activation loop of tyrosine kinase domain are RT frequently found in infant ALL with MLL rearrangements and pediatric ALL RT with hyperdiploidy."; RL Blood 103:1085-1088(2004). RN [33] RP VARIANTS [LARGE SCALE ANALYSIS] ALA-158; MET-227; ASN-324; VAL-358 AND RP ILE-557. 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 [34] RP VARIANT [LARGE SCALE ANALYSIS] MET-194. RX PubMed=18987736; DOI=10.1038/nature07485; RA Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K., RA Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L., RA Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A., RA Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V., RA Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R., RA Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E., RA Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J., Heath S., RA Shannon W.D., Nagarajan R., Walter M.J., Link D.C., Graubert T.A., RA DiPersio J.F., Wilson R.K.; RT "DNA sequencing of a cytogenetically normal acute myeloid leukaemia RT genome."; RL Nature 456:66-72(2008). CC -!- FUNCTION: Tyrosine-protein kinase that acts as a cell-surface receptor CC for the cytokine FLT3LG and regulates differentiation, proliferation CC and survival of hematopoietic progenitor cells and of dendritic cells. CC Promotes phosphorylation of SHC1 and AKT1, and activation of the CC downstream effector MTOR. Promotes activation of RAS signaling and CC phosphorylation of downstream kinases, including MAPK1/ERK2 and/or CC MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, CC PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type CC FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations CC that cause constitutive kinase activity promote cell proliferation and CC resistance to apoptosis via the activation of multiple signaling CC pathways. {ECO:0000269|PubMed:10080542, ECO:0000269|PubMed:11090077, CC ECO:0000269|PubMed:14504097, ECO:0000269|PubMed:16266983, CC ECO:0000269|PubMed:16627759, ECO:0000269|PubMed:18490735, CC ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21067588, CC ECO:0000269|PubMed:21262971, ECO:0000269|PubMed:21516120, CC ECO:0000269|PubMed:7507245}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + CC ADP + H(+); Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- CC COMP:20101, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, CC ChEBI:CHEBI:61978, ChEBI:CHEBI:456216; EC=2.7.10.1; CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, CC ECO:0000269|PubMed:15831474}; CC -!- ACTIVITY REGULATION: Present in an inactive conformation in the absence CC of bound ligand. FLT3LG binding leads to dimerization and activation by CC autophosphorylation. {ECO:0000269|PubMed:14759363, CC ECO:0000269|PubMed:21516120}. CC -!- SUBUNIT: Monomer in the absence of bound FLT3LG. Homodimer in the CC presence of bound FLT3LG. Interacts with FIZ1 following ligand CC activation (By similarity). Interacts with FES, FER, LYN, FGR, HCK, SRC CC and GRB2. Interacts with PTPRJ/DEP-1 and PTPN11/SHP2. Interacts with CC RNF115 and RNF126 (By similarity). {ECO:0000250|UniProtKB:Q00342, CC ECO:0000269|PubMed:10080542, ECO:0000269|PubMed:16684964, CC ECO:0000269|PubMed:20111072, ECO:0000269|PubMed:21262971, CC ECO:0000269|PubMed:21389326, ECO:0000269|PubMed:9737679}. CC -!- SUBUNIT: (Microbial infection) Interacts with human cytomegalovirus CC protein UL7. {ECO:0000269|PubMed:29691342}. CC -!- INTERACTION: CC P36888; P00519: ABL1; NbExp=2; IntAct=EBI-3946257, EBI-375543; CC P36888; P42684: ABL2; NbExp=3; IntAct=EBI-3946257, EBI-1102694; CC P36888; P46108: CRK; NbExp=2; IntAct=EBI-3946257, EBI-886; CC P36888; P46109: CRKL; NbExp=2; IntAct=EBI-3946257, EBI-910; CC P36888; P06241: FYN; NbExp=2; IntAct=EBI-3946257, EBI-515315; CC P36888; Q13322: GRB10; NbExp=6; IntAct=EBI-3946257, EBI-80275; CC P36888; Q9Y6K9: IKBKG; NbExp=2; IntAct=EBI-3946257, EBI-81279; CC P36888; P06239: LCK; NbExp=2; IntAct=EBI-3946257, EBI-1348; CC P36888; P27986: PIK3R1; NbExp=2; IntAct=EBI-3946257, EBI-79464; CC P36888; P20936: RASA1; NbExp=2; IntAct=EBI-3946257, EBI-1026476; CC P36888; P43405: SYK; NbExp=22; IntAct=EBI-3946257, EBI-78302; CC P36888; Q8R4L0: Sla2; Xeno; NbExp=14; IntAct=EBI-3946257, EBI-20766300; CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein. CC Endoplasmic reticulum lumen. Note=Constitutively activated mutant forms CC with internal tandem duplications are less efficiently transported to CC the cell surface and a significant proportion is retained in an CC immature form in the endoplasmic reticulum lumen. The activated kinase CC is rapidly targeted for degradation. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P36888-1; Sequence=Displayed; CC Name=2; CC IsoId=P36888-2; Sequence=VSP_041796; CC -!- TISSUE SPECIFICITY: Detected in bone marrow, in hematopoietic stem CC cells, in myeloid progenitor cells and in granulocyte/macrophage CC progenitor cells (at protein level). Detected in bone marrow, liver, CC thymus, spleen and lymph node, and at low levels in kidney and CC pancreas. Highly expressed in T-cell leukemia. CC {ECO:0000269|PubMed:18490735, ECO:0000269|PubMed:7507245, CC ECO:0000269|PubMed:8394751, ECO:0000269|PubMed:8637232}. CC -!- DOMAIN: The juxtamembrane autoregulatory region is important for normal CC regulation of the kinase activity and for maintaining the kinase in an CC inactive state in the absence of bound ligand. Upon tyrosine CC phosphorylation, it mediates interaction with the SH2 domains of CC numerous signaling partners. In-frame internal tandem duplications CC (ITDs) result in constitutive activation of the kinase. The activity of CC the mutant kinase can be stimulated further by FLT3LG binding. CC -!- PTM: N-glycosylated, contains complex N-glycans with sialic acid. CC {ECO:0000269|PubMed:15831474, ECO:0000269|PubMed:21262971, CC ECO:0000269|PubMed:21389326}. CC -!- PTM: Autophosphorylated on several tyrosine residues in response to CC FLT3LG binding. FLT3LG binding also increases phosphorylation of mutant CC kinases that are constitutively activated. Dephosphorylated by CC PTPRJ/DEP-1, PTPN1, PTPN6/SHP-1, and to a lesser degree by PTPN12. CC Dephosphorylation is important for export from the endoplasmic CC reticulum and location at the cell membrane. CC -!- PTM: Rapidly ubiquitinated by UBE2L6 and the E3 ubiquitin-protein CC ligase SIAH1 after autophosphorylation, leading to its proteasomal CC degradation. {ECO:0000269|PubMed:20508617, CC ECO:0000269|PubMed:21262971}. CC -!- DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of CC acute leukemia, a cancer of the white blood cells. AML is a malignant CC disease of bone marrow characterized by maturational arrest of CC hematopoietic precursors at an early stage of development. Clonal CC expansion of myeloid blasts occurs in bone marrow, blood, and other CC tissue. Myelogenous leukemias develop from changes in cells that CC normally produce neutrophils, basophils, eosinophils and monocytes. CC {ECO:0000269|PubMed:11090077, ECO:0000269|PubMed:11290608, CC ECO:0000269|PubMed:11442493, ECO:0000269|PubMed:14504097, CC ECO:0000269|PubMed:16266983, ECO:0000269|PubMed:18305215, CC ECO:0000269|PubMed:8946930, ECO:0000269|PubMed:9737679}. Note=The gene CC represented in this entry may be involved in disease pathogenesis. CC Somatic mutations that lead to constitutive activation of FLT3 are CC frequent in AML patients. These mutations fall into two classes, the CC most common being in-frame internal tandem duplications of variable CC length in the juxtamembrane region that disrupt the normal regulation CC of the kinase activity. Likewise, point mutations in the activation CC loop of the kinase domain can result in a constitutively activated CC kinase. CC -!- MISCELLANEOUS: Can be used as diagnostic tool to establish the exact CC cause of acute myeloid leukemia, and to determine the optimal therapy. 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 -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/144/FLT3"; 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; U02687; AAA18947.1; -; mRNA. DR EMBL; Z26652; CAA81393.1; -; mRNA. DR EMBL; AL356915; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL445262; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL591024; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471075; EAX08424.1; -; Genomic_DNA. DR EMBL; BC126350; AAI26351.1; -; mRNA. DR EMBL; BC144039; AAI44040.1; -; mRNA. DR EMBL; BC144040; AAI44041.1; -; mRNA. DR EMBL; L36162; AAA35487.1; -; mRNA. DR CCDS; CCDS31953.1; -. [P36888-1] DR PIR; A36873; A36873. DR PIR; A39061; A39061. DR RefSeq; NP_004110.2; NM_004119.3. [P36888-1] DR PDB; 1RJB; X-ray; 2.10 A; A=564-958. DR PDB; 3QS7; X-ray; 4.30 A; E/F/G/H=27-436. DR PDB; 3QS9; X-ray; 7.80 A; E/F/G/H=27-540. DR PDB; 4RT7; X-ray; 3.10 A; A=564-958. DR PDB; 4XUF; X-ray; 3.20 A; A/B=600-947. DR PDB; 5X02; X-ray; 2.40 A; A=564-958. DR PDB; 6IL3; X-ray; 2.50 A; A=564-958. DR PDB; 6JQR; X-ray; 2.20 A; A=571-951. DR PDB; 7QDP; X-ray; 3.69 A; E/F/G/H=1-541. DR PDB; 7ZV9; X-ray; 4.51 A; B/D/F/H/J/L/N/P=1-541. DR PDB; 8XB1; X-ray; 2.85 A; A=564-958. DR PDBsum; 1RJB; -. DR PDBsum; 3QS7; -. DR PDBsum; 3QS9; -. DR PDBsum; 4RT7; -. DR PDBsum; 4XUF; -. DR PDBsum; 5X02; -. DR PDBsum; 6IL3; -. DR PDBsum; 6JQR; -. DR PDBsum; 7QDP; -. DR PDBsum; 7ZV9; -. DR PDBsum; 8XB1; -. DR AlphaFoldDB; P36888; -. DR SMR; P36888; -. DR BioGRID; 108610; 310. DR CORUM; P36888; -. DR DIP; DIP-59769N; -. DR FunCoup; P36888; 883. DR IntAct; P36888; 223. DR MINT; P36888; -. DR STRING; 9606.ENSP00000241453; -. DR BindingDB; P36888; -. DR ChEMBL; CHEMBL1974; -. DR DrugBank; DB12669; 4SC-203. DR DrugBank; DB12746; AKN-028. DR DrugBank; DB12742; Amuvatinib. DR DrugBank; DB11665; BMS-690514. DR DrugBank; DB12267; Brigatinib. DR DrugBank; DB17159; Denfivontinib. DR DrugBank; DB11741; Famitinib. DR DrugBank; DB12500; Fedratinib. DR DrugBank; DB16050; FF-10101-01. DR DrugBank; DB17383; FN-1501. DR DrugBank; DB12010; Fostamatinib. DR DrugBank; DB12141; Gilteritinib. DR DrugBank; DB17140; JNJ-28312141. DR DrugBank; DB06469; Lestaurtinib. DR DrugBank; DB06080; Linifanib. DR DrugBank; DB06595; Midostaurin. DR DrugBank; DB16849; Mivavotinib. DR DrugBank; DB11763; Momelotinib. DR DrugBank; DB09079; Nintedanib. DR DrugBank; DB11697; Pacritinib. DR DrugBank; DB12978; Pexidartinib. DR DrugBank; DB08901; Ponatinib. DR DrugBank; DB15822; Pralsetinib. DR DrugBank; DB12874; Quizartinib. DR DrugBank; DB00398; Sorafenib. DR DrugBank; DB01268; Sunitinib. DR DrugBank; DB05465; Tandutinib. DR DrugBank; DB11800; Tivozanib. DR DrugBank; DB05014; XL999. DR DrugBank; DB00495; Zidovudine. DR DrugCentral; P36888; -. DR GuidetoPHARMACOLOGY; 1807; -. DR GlyCosmos; P36888; 10 sites, No reported glycans. DR GlyGen; P36888; 10 sites, 1 N-linked glycan (1 site). DR iPTMnet; P36888; -. DR PhosphoSitePlus; P36888; -. DR SwissPalm; P36888; -. DR BioMuta; FLT3; -. DR DMDM; 156630887; -. DR CPTAC; CPTAC-2792; -. DR CPTAC; CPTAC-2823; -. DR CPTAC; CPTAC-3121; -. DR CPTAC; CPTAC-3122; -. DR jPOST; P36888; -. DR MassIVE; P36888; -. DR PaxDb; 9606-ENSP00000241453; -. DR PeptideAtlas; P36888; -. DR ProteomicsDB; 55226; -. [P36888-1] DR ProteomicsDB; 55227; -. [P36888-2] DR ABCD; P36888; 40 sequenced antibodies. DR Antibodypedia; 4334; 1624 antibodies from 50 providers. DR DNASU; 2322; -. DR Ensembl; ENST00000241453.12; ENSP00000241453.7; ENSG00000122025.16. [P36888-1] DR GeneID; 2322; -. DR KEGG; hsa:2322; -. DR MANE-Select; ENST00000241453.12; ENSP00000241453.7; NM_004119.3; NP_004110.2. DR UCSC; uc001urw.3; human. [P36888-1] DR AGR; HGNC:3765; -. DR CIViC; 2322; 9 clinical assertions and 217 evidence items across 81 molecular profiles. DR ClinPGx; PA28181; -. DR CTD; 2322; -. DR DisGeNET; 2322; -. DR GeneCards; FLT3; -. DR HGNC; HGNC:3765; FLT3. DR HPA; ENSG00000122025; Tissue enhanced (bone marrow, brain, lymphoid tissue). DR MalaCards; FLT3; -. DR MIM; 136351; gene. DR MIM; 601626; phenotype. DR OpenTargets; ENSG00000122025; -. DR Orphanet; 98834; Acute myeloblastic leukemia with maturation. DR Orphanet; 98833; Acute myeloblastic leukemia without maturation. DR Orphanet; 98829; Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22). DR Orphanet; 98832; Acute myeloid leukemia with minimal differentiation. DR Orphanet; 102724; Acute myeloid leukemia with t(8;21)(q22;q22) translocation. DR Orphanet; 585909; B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2). DR Orphanet; 589534; Mixed phenotype acute leukemia with t(9;22)(q34.1;q11.2). DR Orphanet; 589595; Mixed phenotype acute leukemia with t(v;11q23.3). DR Orphanet; 99861; Precursor T-cell acute lymphoblastic leukemia. DR VEuPathDB; HostDB:ENSG00000122025; -. DR eggNOG; KOG0200; Eukaryota. DR GeneTree; ENSGT00940000160575; -. DR HOGENOM; CLU_000288_49_1_1; -. DR InParanoid; P36888; -. DR OMA; FCDHKHQ; -. DR OrthoDB; 6077854at2759; -. DR PAN-GO; P36888; 9 GO annotations based on evolutionary models. DR PhylomeDB; P36888; -. DR BRENDA; 2.7.10.1; 2681. DR PathwayCommons; P36888; -. DR Reactome; R-HSA-109704; PI3K Cascade. DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling. DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer. DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade. DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. DR Reactome; R-HSA-9607240; FLT3 Signaling. DR Reactome; R-HSA-9645135; STAT5 Activation. DR Reactome; R-HSA-9702509; FLT3 mutants bind TKIs. DR Reactome; R-HSA-9702518; STAT5 activation downstream of FLT3 ITD mutants. DR Reactome; R-HSA-9702569; KW2449-resistant FLT3 mutants. DR Reactome; R-HSA-9702577; semaxanib-resistant FLT3 mutants. DR Reactome; R-HSA-9702581; crenolanib-resistant FLT3 mutants. DR Reactome; R-HSA-9702590; gilteritinib-resistant FLT3 mutants. DR Reactome; R-HSA-9702596; lestaurtinib-resistant FLT3 mutants. DR Reactome; R-HSA-9702600; midostaurin-resistant FLT3 mutants. DR Reactome; R-HSA-9702605; pexidartinib-resistant FLT3 mutants. DR Reactome; R-HSA-9702614; ponatinib-resistant FLT3 mutants. DR Reactome; R-HSA-9702620; quizartinib-resistant FLT3 mutants. DR Reactome; R-HSA-9702624; sorafenib-resistant FLT3 mutants. DR Reactome; R-HSA-9702632; sunitinib-resistant FLT3 mutants. DR Reactome; R-HSA-9702636; tandutinib-resistant FLT3 mutants. DR Reactome; R-HSA-9702998; linifanib-resistant FLT3 mutants. DR Reactome; R-HSA-9703009; tamatinib-resistant FLT3 mutants. DR Reactome; R-HSA-9703648; Signaling by FLT3 ITD and TKD mutants. DR Reactome; R-HSA-9706369; Negative regulation of FLT3. DR Reactome; R-HSA-9706374; FLT3 signaling through SRC family kinases. DR Reactome; R-HSA-9706377; FLT3 signaling by CBL mutants. DR SignaLink; P36888; -. DR SIGNOR; P36888; -. DR Agora; ENSG00000122025; -. DR BioGRID-ORCS; 2322; 22 hits in 1197 CRISPR screens. DR ChiTaRS; FLT3; human. DR EvolutionaryTrace; P36888; -. DR GeneWiki; CD135; -. DR GenomeRNAi; 2322; -. DR Pharos; P36888; Tclin. DR PRO; PR:P36888; -. DR Proteomes; UP000005640; Chromosome 13. DR RNAct; P36888; protein. DR Bgee; ENSG00000122025; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 104 other cell types or tissues. DR ExpressionAtlas; P36888; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA. DR GO; GO:0005788; C:endoplasmic reticulum lumen; IEA:UniProtKB-SubCell. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0043235; C:receptor complex; IBA:GO_Central. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004896; F:cytokine receptor activity; ISS:UniProtKB. DR GO; GO:0019838; F:growth factor binding; IBA:GO_Central. DR GO; GO:0035259; F:nuclear glucocorticoid receptor binding; IEA:Ensembl. DR GO; GO:0141038; F:phosphatidylinositol 3-kinase activator activity; TAS:UniProtKB. DR GO; GO:0004713; F:protein tyrosine kinase activity; TAS:Reactome. DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl. DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central. DR GO; GO:0005021; F:vascular endothelial growth factor receptor activity; TAS:ProtInc. DR GO; GO:0030183; P:B cell differentiation; ISS:UniProtKB. DR GO; GO:0016477; P:cell migration; IBA:GO_Central. DR GO; GO:0007169; P:cell surface receptor protein tyrosine kinase signaling pathway; IBA:GO_Central. DR GO; GO:0071345; P:cellular response to cytokine stimulus; ISS:UniProtKB. DR GO; GO:0071385; P:cellular response to glucocorticoid stimulus; IEA:Ensembl. DR GO; GO:0035726; P:common myeloid progenitor cell proliferation; ISS:UniProtKB. DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0097028; P:dendritic cell differentiation; ISS:UniProtKB. DR GO; GO:0030097; P:hemopoiesis; IDA:MGI. DR GO; GO:0001776; P:leukocyte homeostasis; ISS:UniProtKB. DR GO; GO:0097421; P:liver regeneration; IEA:Ensembl. DR GO; GO:0046651; P:lymphocyte proliferation; ISS:UniProtKB. DR GO; GO:0002318; P:myeloid progenitor cell differentiation; ISS:UniProtKB. DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; TAS:UniProtKB. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IBA:GO_Central. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; TAS:UniProtKB. DR GO; GO:0043410; P:positive regulation of MAPK cascade; TAS:UniProtKB. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; TAS:UniProtKB. DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; TAS:UniProtKB. DR GO; GO:0002328; P:pro-B cell differentiation; ISS:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; TAS:UniProtKB. DR GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB. DR DisProt; DP03756; -. DR FunFam; 2.60.40.10:FF:001159; Fms related tyrosine kinase 3; 1. DR FunFam; 1.10.510.10:FF:000426; Receptor-type tyrosine-protein kinase FLT3; 1. DR FunFam; 2.60.40.10:FF:000661; receptor-type tyrosine-protein kinase FLT3; 1. DR FunFam; 3.30.200.20:FF:000366; receptor-type tyrosine-protein kinase FLT3; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 2. DR Gene3D; 3.30.200.20; Phosphorylase Kinase, domain 1; 1. 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; IPR013151; Immunoglobulin_dom. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR050122; RTK. 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 PANTHER; PTHR24416:SF356; RECEPTOR-TYPE TYROSINE-PROTEIN KINASE FLT3; 1. DR PANTHER; PTHR24416; TYROSINE-PROTEIN KINASE RECEPTOR; 1. DR Pfam; PF00047; ig; 1. DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1. DR PIRSF; PIRSF000615; TyrPK_CSF1-R; 1. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF48726; Immunoglobulin; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR PROSITE; PS50835; IG_LIKE; 1. 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; ATP-binding; Disease variant; KW Disulfide bond; Endoplasmic reticulum; Glycoprotein; KW Host-virus interaction; Immunoglobulin domain; Kinase; Membrane; KW Nucleotide-binding; Phosphoprotein; Proteomics identification; KW Proto-oncogene; Receptor; Reference proteome; Signal; Transferase; KW Transmembrane; Transmembrane helix; Tyrosine-protein kinase; KW Ubl conjugation. FT SIGNAL 1..26 FT /evidence="ECO:0000255" FT CHAIN 27..993 FT /note="Receptor-type tyrosine-protein kinase FLT3" FT /id="PRO_0000016778" FT TOPO_DOM 27..543 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 544..563 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 564..993 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 253..343 FT /note="Ig-like C2-type" FT DOMAIN 610..943 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 591..597 FT /note="Important for normal regulation of the kinase FT activity and for maintaining the kinase in an inactive FT state in the absence of bound ligand" FT ACT_SITE 811 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10028" FT BINDING 616..624 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 644 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000305" FT MOD_RES 572 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:16684964, FT ECO:0000269|PubMed:21262971" FT MOD_RES 574 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:16684964" FT MOD_RES 589 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:16684964, FT ECO:0000269|PubMed:19477218, ECO:0000269|PubMed:21262971" FT MOD_RES 591 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:15831474, FT ECO:0000269|PubMed:16627759, ECO:0000269|PubMed:16684964, FT ECO:0000269|PubMed:19477218, ECO:0000269|PubMed:21262971" FT MOD_RES 599 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:16684964, FT ECO:0000269|PubMed:19477218, ECO:0000269|PubMed:21262971" FT MOD_RES 726 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:16627759, FT ECO:0000269|PubMed:19477218" FT MOD_RES 759 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19369195" FT MOD_RES 768 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:19477218, FT ECO:0000269|PubMed:21262971" FT MOD_RES 793 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:19477218, FT ECO:0000269|PubMed:21262971" FT MOD_RES 842 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:16627759, FT ECO:0000269|PubMed:19477218, ECO:0000269|PubMed:21262971" FT MOD_RES 955 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:16627759, FT ECO:0000269|PubMed:19477218, ECO:0000269|PubMed:21262971" FT MOD_RES 969 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:16627759" FT MOD_RES 993 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19369195" FT CARBOHYD 43 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21389326" FT CARBOHYD 100 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21389326" FT CARBOHYD 151 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21389326" FT CARBOHYD 306 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21389326" FT CARBOHYD 323 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21389326" FT CARBOHYD 351 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21389326" FT CARBOHYD 354 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:21389326" FT CARBOHYD 473 FT /note="N-linked (GlcNAc...) asparagine" FT CARBOHYD 502 FT /note="N-linked (GlcNAc...) asparagine" FT CARBOHYD 541 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 35..65 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:21389326" FT DISULFID 103..114 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:21389326" FT DISULFID 199..206 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:21389326" FT DISULFID 232..241 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:21389326" FT DISULFID 272..330 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:21389326" FT DISULFID 368..407 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:21389326" FT DISULFID 381..392 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:21389326" FT VAR_SEQ 807..847 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_041796" FT VARIANT 7 FT /note="D -> G (in dbSNP:rs12872889)" FT /id="VAR_034677" FT VARIANT 158 FT /note="V -> A (in dbSNP:rs56321896)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042069" FT VARIANT 194 FT /note="V -> M (in dbSNP:rs146030737)" FT /evidence="ECO:0000269|PubMed:18987736" FT /id="VAR_054149" FT VARIANT 227 FT /note="T -> M (in dbSNP:rs1933437)" FT /evidence="ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:8394751, FT ECO:0000269|Ref.4" FT /id="VAR_034678" FT VARIANT 324 FT /note="D -> N (in dbSNP:rs35602083)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042070" FT VARIANT 358 FT /note="D -> V (in dbSNP:rs34172843)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042071" FT VARIANT 417 FT /note="I -> L (in dbSNP:rs56090538)" FT /id="VAR_061291" FT VARIANT 557 FT /note="V -> I (in dbSNP:rs35958982)" FT /evidence="ECO:0000269|PubMed:17344846" FT /id="VAR_042072" FT VARIANT 835 FT /note="D -> E (in acute lymphoblastic leukemia patients and FT acute myelogenous leukemia patients; somatic mutation; FT constitutively activated; dbSNP:rs121913487)" FT /evidence="ECO:0000269|PubMed:11290608, FT ECO:0000269|PubMed:14504097" FT /id="VAR_065679" FT VARIANT 835 FT /note="D -> H (in acute lymphoblastic leukemia patients and FT in acute myelogenous leukemia patients; somatic mutation; FT constitutively activated; dbSNP:rs121913488)" FT /evidence="ECO:0000269|PubMed:11290608, FT ECO:0000269|PubMed:11442493, ECO:0000269|PubMed:14504097" FT /id="VAR_065680" FT VARIANT 835 FT /note="D -> N (in acute lymphoblastic leukemia patients and FT in acute myelogenous leukemia patients; somatic mutation; FT constitutively activated; dbSNP:rs121913488)" FT /evidence="ECO:0000269|PubMed:11290608" FT /id="VAR_065681" FT VARIANT 835 FT /note="D -> V (in acute lymphoblastic leukemia patients and FT in acute myelogenous leukemia patients; somatic mutation; FT constitutively activated; dbSNP:rs121909646)" FT /evidence="ECO:0000269|PubMed:11290608" FT /id="VAR_065682" FT VARIANT 835 FT /note="D -> Y (in acute lymphoblastic leukemia patients and FT in acute myelogenous leukemia patients; somatic mutation; FT constitutively activated; dbSNP:rs121913488)" FT /evidence="ECO:0000269|PubMed:11290608, FT ECO:0000269|PubMed:11442493, ECO:0000269|PubMed:14504097" FT /id="VAR_065683" FT VARIANT 836 FT /note="I -> M (in acute lymphoblastic leukemia patients; FT somatic mutation; dbSNP:rs121913232)" FT /evidence="ECO:0000269|PubMed:14504097" FT /id="VAR_065684" FT MUTAGEN 589 FT /note="Y->F: Reduced phosphorylation of the wild-type FT kinase in response to ligand binding. No effect on the FT phosphorylation of the constitutively activated mutant FT kinase variants. Abolishes activation of STAT5A." FT /evidence="ECO:0000269|PubMed:16627759, FT ECO:0000269|PubMed:16684964, ECO:0000269|PubMed:9737679" FT MUTAGEN 591 FT /note="Y->F: No significant effect on tyrosine FT phosphorylation. Abolishes activation of STAT5A." FT /evidence="ECO:0000269|PubMed:16627759, FT ECO:0000269|PubMed:9737679" FT MUTAGEN 599 FT /note="Y->F: Abolishes interaction with PTPN11/SHP2 and FT phosphorylation of PTPN11/SHP2." FT /evidence="ECO:0000269|PubMed:16684964" FT MUTAGEN 644 FT /note="K->A: Abolishes kinase activity." FT /evidence="ECO:0000269|PubMed:15831474" FT CONFLICT 8 FT /note="G -> A (in Ref. 1; AAA18947)" FT /evidence="ECO:0000305" FT CONFLICT 10..11 FT /note="QL -> TV (in Ref. 1; AAA18947)" FT /evidence="ECO:0000305" FT CONFLICT 71 FT /note="S -> N (in Ref. 5; AAI44040)" FT /evidence="ECO:0000305" FT CONFLICT 78 FT /note="A -> R (in Ref. 2; CAA81393)" FT /evidence="ECO:0000305" FT CONFLICT 346 FT /note="E -> G (in Ref. 1; AAA18947)" FT /evidence="ECO:0000305" FT CONFLICT 940 FT /note="T -> H (in Ref. 6; AAA35487)" FT /evidence="ECO:0000305" FT STRAND 575..581 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 583..585 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 589..591 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 594..596 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 601..603 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 607..609 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 610..618 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 620..631 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 633..636 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 638..646 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 656..668 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 677..681 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 683..686 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 688..692 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 699..704 FT /evidence="ECO:0007829|PDB:1RJB" FT TURN 705..708 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 785..804 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 807..809 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 814..816 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 817..820 FT /evidence="ECO:0007829|PDB:1RJB" FT TURN 821..823 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 824..827 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 831..833 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 836..838 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 842..845 FT /evidence="ECO:0007829|PDB:1RJB" FT STRAND 848..850 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 852..854 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 857..862 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 867..881 FT /evidence="ECO:0007829|PDB:1RJB" FT TURN 882..884 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 896..903 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 916..925 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 930..932 FT /evidence="ECO:0007829|PDB:1RJB" FT HELIX 936..946 FT /evidence="ECO:0007829|PDB:1RJB" SQ SEQUENCE 993 AA; 112903 MW; 6C1995718F352ECE CRC64; MPALARDGGQ LPLLVVFSAM IFGTITNQDL PVIKCVLINH KNNDSSVGKS SSYPMVSESP EDLGCALRPQ SSGTVYEAAA VEVDVSASIT LQVLVDAPGN ISCLWVFKHS SLNCQPHFDL QNRGVVSMVI LKMTETQAGE YLLFIQSEAT NYTILFTVSI RNTLLYTLRR PYFRKMENQD ALVCISESVP EPIVEWVLCD SQGESCKEES PAVVKKEEKV LHELFGTDIR CCARNELGRE CTRLFTIDLN QTPQTTLPQL FLKVGEPLWI RCKAVHVNHG FGLTWELENK ALEEGNYFEM STYSTNRTMI RILFAFVSSV ARNDTGYYTC SSSKHPSQSA LVTIVEKGFI NATNSSEDYE IDQYEEFCFS VRFKAYPQIR CTWTFSRKSF PCEQKGLDNG YSISKFCNHK HQPGEYIFHA ENDDAQFTKM FTLNIRRKPQ VLAEASASQA SCFSDGYPLP SWTWKKCSDK SPNCTEEITE GVWNRKANRK VFGQWVSSST LNMSEAIKGF LVKCCAYNSL GTSCETILLN SPGPFPFIQD NISFYATIGV CLLFIVVLTL LICHKYKKQF RYESQLQMVQ VTGSSDNEYF YVDFREYEYD LKWEFPRENL EFGKVLGSGA FGKVMNATAY GISKTGVSIQ VAVKMLKEKA DSSEREALMS ELKMMTQLGS HENIVNLLGA CTLSGPIYLI FEYCCYGDLL NYLRSKREKF HRTWTEIFKE HNFSFYPTFQ SHPNSSMPGS REVQIHPDSD QISGLHGNSF HSEDEIEYEN QKRLEEEEDL NVLTFEDLLC FAYQVAKGME FLEFKSCVHR DLAARNVLVT HGKVVKICDF GLARDIMSDS NYVVRGNARL PVKWMAPESL FEGIYTIKSD VWSYGILLWE IFSLGVNPYP GIPVDANFYK LIQNGFKMDQ PFYATEEIYI IMQSCWAFDS RKRPSFPNLT SFLGCQLADA EEAMYQNVDG RVSECPHTYQ NRRPFSREMD LGLLSPQAQV EDS //