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P36888 (FLT3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 145. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (8) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Receptor-type tyrosine-protein kinase FLT3

EC=2.7.10.1
Alternative name(s):
FL cytokine receptor
Fetal liver kinase-2
Short name=FLK-2
Fms-like tyrosine kinase 3
Short name=FLT-3
Stem cell tyrosine kinase 1
Short name=STK-1
CD_antigen=CD135
Gene names
Name:FLT3
Synonyms:CD135, FLK2, STK1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length993 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine FLT3LG and regulates differentiation, proliferation and survival of hematopoietic progenitor cells and of dendritic cells. Promotes phosphorylation of SHC1 and AKT1, and activation of the downstream effector MTOR. Promotes activation of RAS signaling and phosphorylation of downstream kinases, including MAPK1/ERK2 and/or MAPK3/ERK1. Promotes phosphorylation of FES, FER, PTPN6/SHP, PTPN11/SHP-2, PLCG1, and STAT5A and/or STAT5B. Activation of wild-type FLT3 causes only marginal activation of STAT5A or STAT5B. Mutations that cause constitutive kinase activity promote cell proliferation and resistance to apoptosis via the activation of multiple signaling pathways. Ref.1 Ref.10 Ref.11 Ref.12 Ref.14 Ref.17 Ref.20 Ref.22 Ref.23 Ref.24 Ref.31

Catalytic activity

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.13

Enzyme regulation

Present in an inactive conformation in the absence of bound ligand. FLT3LG binding leads to dimerization and activation by autophosphorylation. Ref.24 Ref.27

Subunit structure

Monomer in the absence of bound FLT3LG. Homodimer in the presence of bound FLT3LG. Interacts with FIZ1 following ligand activation By similarity. Interacts with FES, FER, LYN, FGR, HCK, SRC and GRB2. Interacts with PTPRJ/DEP-1 and PTPN11/SHP2. Ref.9 Ref.10 Ref.15 Ref.20 Ref.23 Ref.28

Subcellular location

Membrane; Single-pass type I membrane protein. Endoplasmic reticulum lumen. Note: Constitutively activated mutant forms with internal tandem duplications are less efficiently transported to the cell surface and a significant proportion is retained in an immature form in the endoplasmic reticulum lumen. The activated kinase is rapidly targeted for degradation. Ref.7 Ref.13 Ref.17

Tissue specificity

Detected in bone marrow, in hematopoietic stem cells, in myeloid progenitor cells and in granulocyte/macrophage progenitor cells (at protein level). Detected in bone marrow, liver, thymus, spleen and lymph node, and at low levels in kidney and pancreas. Highly expressed in T-cell leukemia. Ref.1 Ref.2 Ref.7 Ref.17

Domain

The juxtamembrane autoregulatory region is important for normal regulation of the kinase activity and for maintaining the kinase in an inactive state in the absence of bound ligand. Upon tyrosine phosphorylation, it mediates interaction with the SH2 domains of numerous signaling partners. In-frame internal tandem duplications (ITDs) result in constitutive activation of the kinase. The activity of the mutant kinase can be stimulated further by FLT3LG binding. Ref.16

Post-translational modification

N-glycosylated, contains complex N-glycans with sialic acid. Ref.13 Ref.23 Ref.28

Autophosphorylated on several tyrosine residues in response to FLT3LG binding. FLT3LG binding also increases phosphorylation of mutant kinases that are constitutively activated. Dephosphorylated by PTPRJ/DEP-1, PTPN1, PTPN6/SHP-1, and to a lesser degree by PTPN12. Dephosphorylation is important for export from the endoplasmic reticulum and location at the cell membrane. Ref.9 Ref.10 Ref.11 Ref.13 Ref.14 Ref.15 Ref.18 Ref.23 Ref.30 Ref.31

Rapidly ubiquitinated by UBE2L6 and the E3 ubiquitin-protein ligase SIAH1 after autophosphorylation, leading to its proteasomal degradation.

Involvement in disease

Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes.
Note: The gene represented in this entry may be involved in disease pathogenesis. Somatic mutations that lead to constitutive activation of FLT3 are frequent in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the activation loop of the kinase domain can result in a constitutively activated kinase. Ref.8 Ref.9 Ref.11 Ref.12 Ref.16 Ref.29 Ref.30 Ref.31

Miscellaneous

Can be used as diagnostic tool to establish the exact cause of acute myeloid leukemia, and to determine the optimal therapy.

Sequence similarities

Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily.

Contains 1 Ig-like C2-type (immunoglobulin-like) domain.

Contains 1 protein kinase domain.

Ontologies

Keywords
   Cellular componentEndoplasmic reticulum
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
Proto-oncogene
   DomainImmunoglobulin domain
Signal
Transmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Receptor
Transferase
Tyrosine-protein kinase
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processB cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to cytokine stimulus

Inferred from sequence or structural similarity. Source: UniProtKB

common myeloid progenitor cell proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

cytokine-mediated signaling pathway

Inferred from sequence or structural similarity. Source: UniProtKB

dendritic cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

hemopoiesis

Inferred from direct assay Ref.1. Source: MGI

leukocyte homeostasis

Inferred from sequence or structural similarity. Source: UniProtKB

lymphocyte proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

myeloid progenitor cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of B cell differentiation

Inferred from electronic annotation. Source: Ensembl

negative regulation of cell proliferation

Inferred from electronic annotation. Source: Ensembl

peptidyl-tyrosine phosphorylation

Traceable author statement Ref.26. Source: UniProtKB

positive regulation of MAP kinase activity

Traceable author statement Ref.26. Source: UniProtKB

positive regulation of MAPK cascade

Traceable author statement Ref.26. Source: UniProtKB

positive regulation of cell proliferation

Traceable author statement Ref.26. Source: UniProtKB

positive regulation of phosphatidylinositol 3-kinase activity

Traceable author statement Ref.25. Source: UniProtKB

positive regulation of phosphatidylinositol 3-kinase signaling

Traceable author statement Ref.25. Source: UniProtKB

positive regulation of tyrosine phosphorylation of STAT protein

Traceable author statement Ref.26. Source: UniProtKB

pro-B cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

pro-T cell differentiation

Inferred from electronic annotation. Source: Ensembl

protein autophosphorylation

Traceable author statement Ref.26. Source: UniProtKB

regulation of apoptotic process

Traceable author statement Ref.26. Source: UniProtKB

transmembrane receptor protein tyrosine kinase signaling pathway

Traceable author statement Ref.1. Source: ProtInc

vascular endothelial growth factor signaling pathway

Traceable author statement Ref.2. Source: GOC

   Cellular_componentcell surface

Inferred from electronic annotation. Source: Ensembl

endoplasmic reticulum lumen

Inferred from electronic annotation. Source: UniProtKB-SubCell

integral component of plasma membrane

Traceable author statement Ref.2. Source: ProtInc

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

cytokine receptor activity

Inferred from sequence or structural similarity. Source: UniProtKB

protein homodimerization activity

Traceable author statement Ref.26. Source: UniProtKB

transmembrane receptor protein tyrosine kinase activity

Traceable author statement Ref.26. Source: UniProtKB

vascular endothelial growth factor-activated receptor activity

Traceable author statement Ref.2. Source: ProtInc

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

IKBKGQ9Y6K92EBI-3946257,EBI-81279
PIK3R1P279862EBI-3946257,EBI-79464

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P36888-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P36888-2)

The sequence of this isoform differs from the canonical sequence as follows:
     807-847: Missing.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2626 Potential
Chain27 – 993967Receptor-type tyrosine-protein kinase FLT3
PRO_0000016778

Regions

Topological domain27 – 543517Extracellular Potential
Transmembrane544 – 56320Helical; Potential
Topological domain564 – 993430Cytoplasmic Potential
Domain253 – 34391Ig-like C2-type
Domain610 – 943334Protein kinase
Nucleotide binding616 – 6249ATP By similarity
Region591 – 5977Important for normal regulation of the kinase activity and for maintaining the kinase in an inactive state in the absence of bound ligand

Sites

Active site8111Proton acceptor By similarity
Binding site6441ATP Probable

Amino acid modifications

Modified residue5721Phosphotyrosine Ref.15 Ref.23
Modified residue5741Phosphoserine Ref.15
Modified residue5891Phosphotyrosine; by autocatalysis Ref.15 Ref.18 Ref.23
Modified residue5911Phosphotyrosine; by autocatalysis Ref.13 Ref.15 Ref.18 Ref.23
Modified residue5991Phosphotyrosine; by autocatalysis Ref.15 Ref.18 Ref.23
Modified residue7261Phosphotyrosine; by autocatalysis Ref.18
Modified residue7591Phosphoserine Ref.19
Modified residue7681Phosphotyrosine Ref.18 Ref.23
Modified residue7931Phosphotyrosine Ref.18 Ref.23
Modified residue8421Phosphotyrosine; by autocatalysis Ref.18 Ref.23
Modified residue9551Phosphotyrosine; by autocatalysis Ref.18 Ref.23
Modified residue9691Phosphotyrosine; by autocatalysis
Modified residue9931Phosphoserine Ref.19
Glycosylation431N-linked (GlcNAc...) Ref.28
Glycosylation1001N-linked (GlcNAc...) Ref.28
Glycosylation1511N-linked (GlcNAc...) Ref.28
Glycosylation3061N-linked (GlcNAc...) Ref.28
Glycosylation3231N-linked (GlcNAc...) Ref.28
Glycosylation3511N-linked (GlcNAc...) Ref.28
Glycosylation3541N-linked (GlcNAc...) Ref.28
Glycosylation4731N-linked (GlcNAc...)
Glycosylation5021N-linked (GlcNAc...)
Glycosylation5411N-linked (GlcNAc...) Potential
Disulfide bond35 ↔ 65 Ref.28
Disulfide bond103 ↔ 114 Ref.28
Disulfide bond199 ↔ 206 Ref.28
Disulfide bond232 ↔ 241 Ref.28
Disulfide bond272 ↔ 330 Ref.28
Disulfide bond368 ↔ 407 Ref.28
Disulfide bond381 ↔ 392 Ref.28

Natural variations

Alternative sequence807 – 84741Missing in isoform 2.
VSP_041796
Natural variant71D → G.
Corresponds to variant rs12872889 [ dbSNP | Ensembl ].
VAR_034677
Natural variant1581V → A. Ref.32
Corresponds to variant rs56321896 [ dbSNP | Ensembl ].
VAR_042069
Natural variant1941V → M. Ref.33
VAR_054149
Natural variant2271T → M. Ref.2 Ref.4 Ref.5 Ref.32
Corresponds to variant rs1933437 [ dbSNP | Ensembl ].
VAR_034678
Natural variant3241D → N. Ref.32
Corresponds to variant rs35602083 [ dbSNP | Ensembl ].
VAR_042070
Natural variant3581D → V. Ref.32
Corresponds to variant rs34172843 [ dbSNP | Ensembl ].
VAR_042071
Natural variant4171I → L.
Corresponds to variant rs56090538 [ dbSNP | Ensembl ].
VAR_061291
Natural variant5571V → I. Ref.32
Corresponds to variant rs35958982 [ dbSNP | Ensembl ].
VAR_042072
Natural variant8351D → E in acute lymphoblastic leukemia patients and in acute myelogenous leukemia patients; somatic mutation; constitutively activated. Ref.30 Ref.31
VAR_065679
Natural variant8351D → H in acute lymphoblastic leukemia patients and in acute myelogenous leukemia patients; somatic mutation; constitutively activated. Ref.29 Ref.30 Ref.31
VAR_065680
Natural variant8351D → N in acute lymphoblastic leukemia patients and in acute myelogenous leukemia patients; somatic mutation; constitutively activated. Ref.30
VAR_065681
Natural variant8351D → V in acute lymphoblastic leukemia patients and in acute myelogenous leukemia patients; somatic mutation; constitutively activated. Ref.30
VAR_065682
Natural variant8351D → Y in acute lymphoblastic leukemia patients and in acute myelogenous leukemia patients; somatic mutation; constitutively activated. Ref.29 Ref.30 Ref.31
VAR_065683
Natural variant8361I → M in acute lymphoblastic leukemia patients; somatic mutation. Ref.31
VAR_065684

Experimental info

Mutagenesis5891Y → F: Reduced phosphorylation of the wild-type kinase in response to ligand binding. No effect on the phosphorylation of the constitutively activated mutant kinase variants. Abolishes activation of STAT5A. Ref.9 Ref.14 Ref.15
Mutagenesis5911Y → F: No significant effect on tyrosine phosphorylation. Abolishes activation of STAT5A. Ref.9 Ref.14
Mutagenesis5991Y → F: Abolishes interaction with PTPN11/SHP2 and phosphorylation of PTPN11/SHP2. Ref.15
Mutagenesis6441K → A: Abolishes kinase activity. Ref.13
Sequence conflict81G → A in AAA18947. Ref.1
Sequence conflict10 – 112QL → TV in AAA18947. Ref.1
Sequence conflict711S → N in AAI44040. Ref.5
Sequence conflict781A → R in CAA81393. Ref.2
Sequence conflict3461E → G in AAA18947. Ref.1
Sequence conflict9401T → H in AAA35487. Ref.6

Secondary structure

......................................................... 993
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified August 21, 2007. Version 2.
Checksum: 6C1995718F352ECE

FASTA993112,903
        10         20         30         40         50         60 
MPALARDGGQ LPLLVVFSAM IFGTITNQDL PVIKCVLINH KNNDSSVGKS SSYPMVSESP 

        70         80         90        100        110        120 
EDLGCALRPQ SSGTVYEAAA VEVDVSASIT LQVLVDAPGN ISCLWVFKHS SLNCQPHFDL 

       130        140        150        160        170        180 
QNRGVVSMVI LKMTETQAGE YLLFIQSEAT NYTILFTVSI RNTLLYTLRR PYFRKMENQD 

       190        200        210        220        230        240 
ALVCISESVP EPIVEWVLCD SQGESCKEES PAVVKKEEKV LHELFGTDIR CCARNELGRE 

       250        260        270        280        290        300 
CTRLFTIDLN QTPQTTLPQL FLKVGEPLWI RCKAVHVNHG FGLTWELENK ALEEGNYFEM 

       310        320        330        340        350        360 
STYSTNRTMI RILFAFVSSV ARNDTGYYTC SSSKHPSQSA LVTIVEKGFI NATNSSEDYE 

       370        380        390        400        410        420 
IDQYEEFCFS VRFKAYPQIR CTWTFSRKSF PCEQKGLDNG YSISKFCNHK HQPGEYIFHA 

       430        440        450        460        470        480 
ENDDAQFTKM FTLNIRRKPQ VLAEASASQA SCFSDGYPLP SWTWKKCSDK SPNCTEEITE 

       490        500        510        520        530        540 
GVWNRKANRK VFGQWVSSST LNMSEAIKGF LVKCCAYNSL GTSCETILLN SPGPFPFIQD 

       550        560        570        580        590        600 
NISFYATIGV CLLFIVVLTL LICHKYKKQF RYESQLQMVQ VTGSSDNEYF YVDFREYEYD 

       610        620        630        640        650        660 
LKWEFPRENL EFGKVLGSGA FGKVMNATAY GISKTGVSIQ VAVKMLKEKA DSSEREALMS 

       670        680        690        700        710        720 
ELKMMTQLGS HENIVNLLGA CTLSGPIYLI FEYCCYGDLL NYLRSKREKF HRTWTEIFKE 

       730        740        750        760        770        780 
HNFSFYPTFQ SHPNSSMPGS REVQIHPDSD QISGLHGNSF HSEDEIEYEN QKRLEEEEDL 

       790        800        810        820        830        840 
NVLTFEDLLC FAYQVAKGME FLEFKSCVHR DLAARNVLVT HGKVVKICDF GLARDIMSDS 

       850        860        870        880        890        900 
NYVVRGNARL PVKWMAPESL FEGIYTIKSD VWSYGILLWE IFSLGVNPYP GIPVDANFYK 

       910        920        930        940        950        960 
LIQNGFKMDQ PFYATEEIYI IMQSCWAFDS RKRPSFPNLT SFLGCQLADA EEAMYQNVDG 

       970        980        990 
RVSECPHTYQ NRRPFSREMD LGLLSPQAQV EDS 

« Hide

Isoform 2 [UniParc].

Checksum: 1C384B292EDEB144
Show »

FASTA952108,378

References

« Hide 'large scale' references
[1]"STK-1, the human homolog of Flk-2/Flt-3, is selectively expressed in CD34+ human bone marrow cells and is involved in the proliferation of early progenitor/stem cells."
Small D., Levenstein M., Kim E., Carow C., Amin S., Rockwell P., Witte L., Burrow C., Ratajczak M.Z., Gewirtz A.M., Civin C.I.
Proc. Natl. Acad. Sci. U.S.A. 91:459-463(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY.
Tissue: Bone marrow.
[2]"Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells."
Rosnet O., Schiff C., Pebusque M.J., Marchetto S., Tonnelle C., Toiron Y., Birg F., Birnbaum D.
Blood 82:1110-1119(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, VARIANT MET-227.
Tissue: Lymphocyte.
[3]"The DNA sequence and analysis of human chromosome 13."
Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L., Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P., Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L., Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S., Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.
Nature 428:522-528(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT MET-227.
[5]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), VARIANT MET-227.
[6]"Isolation and chromosomal localization of a novel FMS-like tyrosine kinase gene."
Rosnet O., Mattei M.-G., Marchetto S., Birnbaum D.
Genomics 9:380-385(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 783-942 (ISOFORM 1).
Tissue: Testis.
[7]"Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells."
Rosnet O., Buhring H.J., Marchetto S., Rappold I., Lavagna C., Sainty D., Arnoulet C., Chabannon C., Kanz L., Hannum C., Birnbaum D.
Leukemia 10:238-248(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[8]"Internal tandem duplication of the flt3 gene found in acute myeloid leukemia."
Nakao M., Yokota S., Iwai T., Kaneko H., Horiike S., Kashima K., Sonoda Y., Fujimoto T., Misawa S.
Leukemia 10:1911-1918(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN AML.
[9]"Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product."
Kiyoi H., Towatari M., Yokota S., Hamaguchi M., Ohno R., Saito H., Naoe T.
Leukemia 12:1333-1337(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN AML, SUBUNIT, PHOSPHORYLATION, MUTAGENESIS OF TYR-589 AND TYR-591.
[10]"Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells."
Zhang S., Mantel C., Broxmeyer H.E.
J. Leukoc. Biol. 65:372-380(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PROMOTING PHOSPHORYLATION OF SHC1; PTPN6/SHP; PTPN11/SHP-2; MAPK1/ERK2; MAPK3/ERK1, AUTOPHOSPHORYLATION, INTERACTION WITH GRB2.
[11]"Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways."
Mizuki M., Fenski R., Halfter H., Matsumura I., Schmidt R., Muller C., Gruning W., Kratz-Albers K., Serve S., Steur C., Buchner T., Kienast J., Kanakura Y., Berdel W.E., Serve H.
Blood 96:3907-3914(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACTIVATION OF AKT1; MAPK1/ERK2; MAPK3/ERK1; STAT5A AND STAT5B, PHOSPHORYLATION, FUNCTION IN ACTIVATION OF THE RAS PATHWAY, INVOLVEMENT IN AML.
[12]"Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation."
Brandts C.H., Sargin B., Rode M., Biermann C., Lindtner B., Schwable J., Buerger H., Muller-Tidow C., Choudhary C., McMahon M., Berdel W.E., Serve H.
Cancer Res. 65:9643-9650(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACTIVATION OF AKT1, INVOLVEMENT IN AML.
[13]"Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases."
Schmidt-Arras D.E., Bohmer A., Markova B., Choudhary C., Serve H., Bohmer F.D.
Mol. Cell. Biol. 25:3690-3703(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, CATALYTIC ACTIVITY, PHOSPHORYLATION AT TYR-591, DEPHOSPHORYLATION BY PTPN1; PTPN6/SHP-1 AND PTPN12, PROTEASOMAL DEGRADATION, GLYCOSYLATION, MUTAGENESIS OF LYS-644.
[14]"Roles of tyrosine 589 and 591 in STAT5 activation and transformation mediated by FLT3-ITD."
Rocnik J.L., Okabe R., Yu J.C., Lee B.H., Giese N., Schenkein D.P., Gilliland D.G.
Blood 108:1339-1345(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACTIVATION OF STAT5A AND/OR STAT5B, AUTOPHOSPHORYLATION, IDENTIFICATION BY MASS SPECTROMETRY, MUTAGENESIS OF TYR-589 AND TYR-591.
[15]"Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2."
Heiss E., Masson K., Sundberg C., Pedersen M., Sun J., Bengtsson S., Ronnstrand L.
Blood 108:1542-1550(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PTPN11/SHP2; LYN; FGR; HCK AND SRC, AUTOPHOSPHORYLATION, MUTAGENESIS OF TYR-589 AND TYR-599, PHOSPHORYLATION AT TYR-572; SER-574; TYR-589; TYR-591 AND TYR-599.
[16]"Structural and numerical variation of FLT3/ITD in pediatric AML."
Meshinchi S., Stirewalt D.L., Alonzo T.A., Boggon T.J., Gerbing R.B., Rocnik J.L., Lange B.J., Gilliland D.G., Radich J.P.
Blood 111:4930-4933(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: REGION INVOLVED IN REGULATION OF KINASE ACTIVITY, AUTOREGULATORY DOMAIN, INVOLVEMENT IN AML.
[17]"Human Flt3 is expressed at the hematopoietic stem cell and the granulocyte/macrophage progenitor stages to maintain cell survival."
Kikushige Y., Yoshimoto G., Miyamoto T., Iino T., Mori Y., Iwasaki H., Niiro H., Takenaka K., Nagafuji K., Harada M., Ishikawa F., Akashi K.
J. Immunol. 180:7358-7367(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
[18]"Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation."
Razumovskaya E., Masson K., Khan R., Bengtsson S., Ronnstrand L.
Exp. Hematol. 37:979-989(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT TYR-589; TYR-591; TYR-599; TYR-726; TYR-768; TYR-793; TYR-842 AND TYR-955.
[19]"Large-scale proteomics analysis of the human kinome."
Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H.
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-759 AND SER-993, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[20]"FES kinases are required for oncogenic FLT3 signaling."
Voisset E., Lopez S., Chaix A., Georges C., Hanssens K., Prebet T., Dubreuil P., De Sepulveda P.
Leukemia 24:721-728(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACTIVATION OF FES AND FER, INTERACTION WITH FES AND FER.
[21]"Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradation."
Buchwald M., Pietschmann K., Muller J.P., Bohmer F.D., Heinzel T., Kramer O.H.
Leukemia 24:1412-1421(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION.
[22]"mTOR signaling is activated by FLT3 kinase and promotes survival of FLT3-mutated acute myeloid leukemia cells."
Chen W., Drakos E., Grammatikakis I., Schlette E.J., Li J., Leventaki V., Staikou-Drakopoulou E., Patsouris E., Panayiotidis P., Medeiros L.J., Rassidakis G.Z.
Mol. Cancer 9:292-292(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[23]"Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling."
Arora D., Stopp S., Bohmer S.A., Schons J., Godfrey R., Masson K., Razumovskaya E., Ronnstrand L., Tanzer S., Bauer R., Bohmer F.D., Muller J.P.
J. Biol. Chem. 286:10918-10929(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PTPRJ/DEP1, FUNCTION IN ACTIVATION OF MAPK1/ERK2; MAPK3/ERK1; PLCG1; STAT5A AND/OR STAT5B, GLYCOSYLATION, UBIQUITINATION, PHOSPHORYLATION AT TYR-572; TYR-589; TYR-591; TYR-599; TYR-768; TYR-793; TYR-842 AND TYR-955.
[24]"Further activation of FLT3 mutants by FLT3 ligand."
Zheng R., Bailey E., Nguyen B., Yang X., Piloto O., Levis M., Small D.
Oncogene 30:4004-4014(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION.
[25]"The role of FLT3 in haematopoietic malignancies."
Stirewalt D.L., Radich J.P.
Nat. Rev. Cancer 3:650-665(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[26]"Structural and functional alterations of FLT3 in acute myeloid leukemia."
Meshinchi S., Appelbaum F.R.
Clin. Cancer Res. 15:4263-4269(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[27]"The structural basis for autoinhibition of FLT3 by the juxtamembrane domain."
Griffith J., Black J., Faerman C., Swenson L., Wynn M., Lu F., Lippke J., Saxena K.
Mol. Cell 13:169-178(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 564-958, ENZYME REGULATION.
[28]"Structural insights into the extracellular assembly of the hematopoietic Flt3 signaling complex."
Verstraete K., Vandriessche G., Januar M., Elegheert J., Shkumatov A.V., Desfosses A., Van Craenenbroeck K., Svergun D.I., Gutsche I., Vergauwen B., Savvides S.N.
Blood 118:60-68(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (4.3 ANGSTROMS) OF 27-436 IN COMPLEX WITH FLT3LG, SUBUNIT, INTERACTION WITH FLT3LG, GLYCOSYLATION AT ASN-43; ASN-100; ASN-151; ASN-306; ASN-323; ASN-351 AND ASN-354, IDENTIFICATION BY MASS SPECTROMETRY, DISULFIDE BONDS.
[29]"Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia."
Abu-Duhier F.M., Goodeve A.C., Wilson G.A., Care R.S., Peake I.R., Reilly J.T.
Br. J. Haematol. 113:983-988(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS TYR-835 DEL; HIS-835 AND TYR-835, INVOLVEMENT IN AML.
[30]"Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies."
Yamamoto Y., Kiyoi H., Nakano Y., Suzuki R., Kodera Y., Miyawaki S., Asou N., Kuriyama K., Yagasaki F., Shimazaki C., Akiyama H., Saito K., Nishimura M., Motoji T., Shinagawa K., Takeshita A., Saito H., Ueda R., Ohno R., Naoe T.
Blood 97:2434-2439(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS ASN-835; GLU-835; HIS-835; VAL-835 AND TYR-835, CHARACTERIZATION OF VARIANTS ASN-835; GLU-835; HIS-835; VAL-835 AND TYR-835, PHOSPHORYLATION, INVOLVEMENT IN AML.
[31]"FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy."
Taketani T., Taki T., Sugita K., Furuichi Y., Ishii E., Hanada R., Tsuchida M., Sugita K., Ida K., Hayashi Y.
Blood 103:1085-1088(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS GLU-835; HIS-835; TYR-835; ILE-836 DEL AND MET-836, FUNCTION IN ACTIVATION OF STAT5A AND/OR STAT5B, PHOSPHORYLATION, INVOLVEMENT IN AML.
[32]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] ALA-158; MET-227; ASN-324; VAL-358 AND ILE-557.
[33]"DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome."
Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K., Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L., Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A., Abbott S. expand/collapse author list , Locke D., Hillier L.W., Miner T., Fulton L., Magrini V., Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R., Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E., Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J., Heath S., Shannon W.D., Nagarajan R., Walter M.J., Link D.C., Graubert T.A., DiPersio J.F., Wilson R.K.
Nature 456:66-72(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT [LARGE SCALE ANALYSIS] MET-194.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U02687 mRNA. Translation: AAA18947.1.
Z26652 mRNA. Translation: CAA81393.1.
AL356915 Genomic DNA. No translation available.
AL445262 Genomic DNA. No translation available.
AL591024 Genomic DNA. No translation available.
CH471075 Genomic DNA. Translation: EAX08424.1.
BC126350 mRNA. Translation: AAI26351.1.
BC144039 mRNA. Translation: AAI44040.1.
BC144040 mRNA. Translation: AAI44041.1.
L36162 mRNA. Translation: AAA35487.1.
PIRA36873.
A39061.
RefSeqNP_004110.2. NM_004119.2.
UniGeneHs.507590.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1RJBX-ray2.10A564-958[»]
3QS7X-ray4.30E/F/G/H27-436[»]
3QS9X-ray7.80E/F/G/H27-540[»]
DisProtDP00312.
ProteinModelPortalP36888.
SMRP36888. Positions 79-529, 572-975.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108610. 13 interactions.
DIPDIP-59769N.
IntActP36888. 3 interactions.
MINTMINT-7103562.
STRING9606.ENSP00000241453.

Chemistry

BindingDBP36888.
ChEMBLCHEMBL1974.
DrugBankDB00398. Sorafenib.
DB01268. Sunitinib.
GuidetoPHARMACOLOGY1807.

PTM databases

PhosphoSiteP36888.

Polymorphism databases

DMDM156630887.

Proteomic databases

PaxDbP36888.
PRIDEP36888.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000241453; ENSP00000241453; ENSG00000122025. [P36888-1]
ENST00000537084; ENSP00000438139; ENSG00000122025. [P36888-2]
GeneID2322.
KEGGhsa:2322.
UCSCuc001urw.3. human. [P36888-1]
uc010tdn.2. human. [P36888-2]

Organism-specific databases

CTD2322.
GeneCardsGC13M028577.
H-InvDBHIX0037338.
HGNCHGNC:3765. FLT3.
HPACAB018358.
MIM136351. gene.
601626. phenotype.
neXtProtNX_P36888.
Orphanet98837. Acute biphenotypic leukemia.
98834. Acute myeloblastic leukemia with maturation.
98833. Acute myeloblastic leukemia without maturation.
98829. Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22).
102724. Acute myeloid leukemia with t(8;21)(q22;q22) translocation.
517. Acute myelomonocytic leukemia.
98832. Minimally differentiated acute myeloblastic leukemia.
99860. Precursor B-cell acute lymphoblastic leukemia.
99861. Precursor T-cell acute lymphoblastic leukemia.
PharmGKBPA28181.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOVERGENHBG005735.
KOK05092.
OrthoDBEOG7H792D.
PhylomeDBP36888.
TreeFamTF325768.

Enzyme and pathway databases

BRENDA2.7.10.1. 2681.
SignaLinkP36888.

Gene expression databases

ArrayExpressP36888.
BgeeP36888.
CleanExHS_FLT3.
GenevestigatorP36888.

Family and domain databases

Gene3D2.60.40.10. 2 hits.
InterProIPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR003599. Ig_sub.
IPR013151. Immunoglobulin.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR016243. Tyr_kinase_CSF1/PDGF_rcpt.
IPR001824. Tyr_kinase_rcpt_3_CS.
[Graphical view]
PfamPF00047. ig. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PIRSFPIRSF000615. TyrPK_CSF1-R. 1 hit.
SMARTSM00409. IG. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 2 hits.
PROSITEPS50835. IG_LIKE. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS00240. RECEPTOR_TYR_KIN_III. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP36888.
GeneWikiCD135.
GenomeRNAi2322.
NextBio9425.
PROP36888.
SOURCESearch...

Entry information

Entry nameFLT3_HUMAN
AccessionPrimary (citable) accession number: P36888
Secondary accession number(s): A0AVG9 expand/collapse secondary AC list , B7ZLT7, B7ZLT8, F5H0A0, Q13414
Entry history
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: August 21, 2007
Last modified: April 16, 2014
This is version 145 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 13

Human chromosome 13: entries, gene names and cross-references to MIM

Human cell differentiation molecules

CD nomenclature of surface proteins of human leucocytes and list of entries