FLT3_HUMAN
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 03-AUG-2022, entry version 208.
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 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=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: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="http://atlasgeneticsoncology.org/Genes/FLT3ID144.html";
CC ---------------------------------------------------------------------------
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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_004119.2. [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 PDBsum; 1RJB; -.
DR PDBsum; 3QS7; -.
DR PDBsum; 3QS9; -.
DR PDBsum; 4RT7; -.
DR PDBsum; 4XUF; -.
DR PDBsum; 5X02; -.
DR PDBsum; 6IL3; -.
DR PDBsum; 6JQR; -.
DR AlphaFoldDB; P36888; -.
DR SMR; P36888; -.
DR BioGRID; 108610; 141.
DR DIP; DIP-59769N; -.
DR IntAct; P36888; 66.
DR MINT; P36888; -.
DR STRING; 9606.ENSP00000241453; -.
DR BindingDB; P36888; -.
DR ChEMBL; CHEMBL1974; -.
DR DrugBank; DB12742; Amuvatinib.
DR DrugBank; DB12267; Brigatinib.
DR DrugBank; DB12500; Fedratinib.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB12141; Gilteritinib.
DR DrugBank; DB06469; Lestaurtinib.
DR DrugBank; DB06080; Linifanib.
DR DrugBank; DB06595; Midostaurin.
DR DrugBank; DB09079; Nintedanib.
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 DrugCentral; P36888; -.
DR GuidetoPHARMACOLOGY; 1807; -.
DR GlyGen; P36888; 10 sites.
DR iPTMnet; P36888; -.
DR PhosphoSitePlus; P36888; -.
DR BioMuta; FLT3; -.
DR DMDM; 156630887; -.
DR CPTAC; CPTAC-2792; -.
DR jPOST; P36888; -.
DR MassIVE; P36888; -.
DR MaxQB; P36888; -.
DR PaxDb; P36888; -.
DR PeptideAtlas; P36888; -.
DR PRIDE; P36888; -.
DR ProteomicsDB; 55226; -. [P36888-1]
DR ProteomicsDB; 55227; -. [P36888-2]
DR ABCD; P36888; 40 sequenced antibodies.
DR Antibodypedia; 4334; 1585 antibodies from 51 providers.
DR DNASU; 2322; -.
DR Ensembl; ENST00000241453.12; ENSP00000241453.7; ENSG00000122025.15. [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 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 neXtProt; NX_P36888; -.
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; 585877; B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality.
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 PharmGKB; PA28181; -.
DR VEuPathDB; HostDB:ENSG00000122025; -.
DR eggNOG; KOG0200; Eukaryota.
DR GeneTree; ENSGT00940000160575; -.
DR HOGENOM; CLU_000288_49_1_1; -.
DR InParanoid; P36888; -.
DR OMA; EVQIHQD; -.
DR OrthoDB; 719800at2759; -.
DR PhylomeDB; P36888; -.
DR TreeFam; TF325768; -.
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 BioGRID-ORCS; 2322; 21 hits in 1107 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 cerebellar hemisphere and 103 other tissues.
DR ExpressionAtlas; P36888; baseline and differential.
DR Genevisible; P36888; HS.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
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:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
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:0043621; F:protein self-association; IMP:CAFA.
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:0031100; P:animal organ regeneration; IEA:Ensembl.
DR GO; GO:0030183; P:B cell differentiation; ISS:UniProtKB.
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: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; TAS:UniProtKB.
DR GO; GO:0033674; P:positive regulation of kinase activity; 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:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; TAS:UniProtKB.
DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; 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 GO; GO:0010243; P:response to organonitrogen compound; IEA:Ensembl.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR030118; FLT3.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
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 PANTHER; PTHR24416:SF356; PTHR24416:SF356; 1.
DR Pfam; PF00047; ig; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF48726; SSF48726; 1.
DR SUPFAM; SSF56112; SSF56112; 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; Proto-oncogene; Receptor;
KW Reference proteome; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase; 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
