P36888 (FLT3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	993 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 component	Endoplasmic reticulum Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Proto-oncogene
Domain	Immunoglobulin domain Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	B cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB common myeloid progenitor cell proliferation Inferred from sequence or structural similarity. Source: UniProtKB dendritic cell differentiation Inferred from sequence or structural similarity. Source: UniProtKB 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: Compara negative regulation of cell proliferation Inferred from electronic annotation. Source: Compara 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 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 cascade 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: Compara protein autophosphorylation Traceable author statement Ref.26. Source: UniProtKB regulation of apoptotic process Traceable author statement Ref.26. Source: UniProtKB
Cellular_component	cell surface Inferred from electronic annotation. Source: Compara endoplasmic reticulum lumen Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Traceable author statement Ref.2. Source: ProtInc
Molecular_function	ATP 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 vascular endothelial growth factor-activated receptor activity Traceable author statement Ref.2. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
IKBKG	Q9Y6K9	2	EBI-3946257,EBI-81279

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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 26

26

Potential

Chain

27 – 993

967

Receptor-type tyrosine-protein kinase FLT3

PRO_0000016778

Regions

Topological domain

27 – 543

517

Extracellular Potential

Transmembrane

544 – 563

20

Helical; Potential

Topological domain

564 – 993

430

Cytoplasmic Potential

Domain

253 – 343

91

Ig-like C2-type

Domain

610 – 943

334

Protein kinase

Nucleotide binding

616 – 624

9

ATP By similarity

Region

591 – 597

7

Important for normal regulation of the kinase activity and for maintaining the kinase in an inactive state in the absence of bound ligand

Sites

Active site

811

1

Proton acceptor By similarity

Binding site

644

1

ATP Probable

Amino acid modifications

Modified residue

572

1

Phosphotyrosine Ref.15 Ref.23

Modified residue

574

1

Phosphoserine Ref.15

Modified residue

589

1

Phosphotyrosine; by autocatalysis Ref.15 Ref.18 Ref.23

Modified residue

591

1

Phosphotyrosine; by autocatalysis Ref.13 Ref.15 Ref.18 Ref.23

Modified residue

599

1

Phosphotyrosine; by autocatalysis Ref.15 Ref.18 Ref.23

Modified residue

726

1

Phosphotyrosine; by autocatalysis Ref.18

Modified residue

759

1

Phosphoserine Ref.19

Modified residue

768

1

Phosphotyrosine Ref.18 Ref.23

Modified residue

793

1

Phosphotyrosine Ref.18 Ref.23

Modified residue

842

1

Phosphotyrosine; by autocatalysis Ref.18 Ref.23

Modified residue

955

1

Phosphotyrosine; by autocatalysis Ref.18 Ref.23

Modified residue

969

1

Phosphotyrosine; by autocatalysis

Modified residue

993

1

Phosphoserine Ref.19

Glycosylation

43

1

N-linked (GlcNAc...) Ref.28

Glycosylation

100

1

N-linked (GlcNAc...) Ref.28

Glycosylation

151

1

N-linked (GlcNAc...) Ref.28

Glycosylation

306

1

N-linked (GlcNAc...) Ref.28

Glycosylation

323

1

N-linked (GlcNAc...) Ref.28

Glycosylation

351

1

N-linked (GlcNAc...) Ref.28

Glycosylation

354

1

N-linked (GlcNAc...) Ref.28

Glycosylation

473

1

N-linked (GlcNAc...)

Glycosylation

502

1

N-linked (GlcNAc...)

Glycosylation

541

1

N-linked (GlcNAc...) Potential

Disulfide bond

35 ↔ 65

Ref.28

Disulfide bond

103 ↔ 114

Ref.28

Disulfide bond

199 ↔ 206

Ref.28

Disulfide bond

232 ↔ 241

Ref.28

Disulfide bond

272 ↔ 330

Ref.28

Disulfide bond

368 ↔ 407

Ref.28

Disulfide bond

381 ↔ 392

Ref.28

Natural variations

Alternative sequence

807 – 847

41

Missing in isoform 2.

VSP_041796

Natural variant

7

1

D → G.
Corresponds to variant rs12872889 [ dbSNP | Ensembl ].

VAR_034677

Natural variant

158

1

V → A. Ref.32
Corresponds to variant rs56321896 [ dbSNP | Ensembl ].

VAR_042069

Natural variant

194

1

V → M. Ref.33

VAR_054149

Natural variant

227

1

T → M. Ref.2 Ref.4 Ref.5 Ref.32
Corresponds to variant rs1933437 [ dbSNP | Ensembl ].

VAR_034678

Natural variant

324

1

D → N. Ref.32
Corresponds to variant rs35602083 [ dbSNP | Ensembl ].

VAR_042070

Natural variant

358

1

D → V. Ref.32
Corresponds to variant rs34172843 [ dbSNP | Ensembl ].

VAR_042071

Natural variant

417

1

I → L.
Corresponds to variant rs56090538 [ dbSNP | Ensembl ].

VAR_061291

Natural variant

557

1

V → I. Ref.32
Corresponds to variant rs35958982 [ dbSNP | Ensembl ].

VAR_042072

Natural variant

835

1

D → E in acute lymphoblastic leukemia patients and in acute myelogenous leukemia patients; somatic mutation; constitutively activated. Ref.30 Ref.31

VAR_065679

Natural variant

835

1

D → 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 variant

835

1

D → N in acute lymphoblastic leukemia patients and in acute myelogenous leukemia patients; somatic mutation; constitutively activated. Ref.30

VAR_065681

Natural variant

835

1

D → V in acute lymphoblastic leukemia patients and in acute myelogenous leukemia patients; somatic mutation; constitutively activated. Ref.30

VAR_065682

Natural variant

835

1

D → 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 variant

836

1

I → M in acute lymphoblastic leukemia patients; somatic mutation. Ref.31

VAR_065684

Experimental info

Mutagenesis

589

1

Y → 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

Mutagenesis

591

1

Y → F: No significant effect on tyrosine phosphorylation. Abolishes activation of STAT5A. Ref.9 Ref.14

Mutagenesis

599

1

Y → F: Abolishes interaction with PTPN11/SHP2 and phosphorylation of PTPN11/SHP2. Ref.15

Mutagenesis

644

1

K → A: Abolishes kinase activity. Ref.13

Sequence conflict

8

1

G → A in AAA18947. Ref.1

Sequence conflict

10 – 11

2

QL → TV in AAA18947. Ref.1

Sequence conflict

71

1

S → N in AAI44040. Ref.5

Sequence conflict

78

1

A → R in CAA81393. Ref.2

Sequence conflict

346

1

E → G in AAA18947. Ref.1

Sequence conflict

940

1

T → H in AAA35487. Ref.6

Secondary structure

1

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993

Helix Strand Turn

Details...

Beta strand

575 – 581

7

Beta strand

583 – 585

3

Beta strand

589 – 591

3

Helix

594 – 596

3

Helix

601 – 603

3

Helix

607 – 609

3

Beta strand

610 – 618

9

Beta strand

620 – 631

12

Beta strand

633 – 636

4

Beta strand

638 – 646

9

Helix

656 – 668

13

Beta strand

677 – 681

5

Beta strand

683 – 686

4

Beta strand

688 – 692

5

Helix

699 – 704

6

Turn

705 – 708

4

Helix

785 – 804

20

Beta strand

807 – 809

3

Helix

814 – 816

3

Beta strand

817 – 820

4

Turn

821 – 823

3

Beta strand

824 – 827

4

Helix

831 – 833

3

Helix

836 – 838

3

Beta strand

842 – 845

4

Beta strand

848 – 850

3

Helix

852 – 854

3

Helix

857 – 862

6

Helix

867 – 881

15

Turn

882 – 884

3

Helix

896 – 903

8

Helix

916 – 925

10

Helix

930 – 932

3

Helix

936 – 946

11

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified August 21, 2007. Version 2. Checksum: 6C1995718F352ECE	FASTA	993	112,903
	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
	Isoform 2 [UniParc]. Checksum: 1C384B292EDEB144	FASTA	952	108,378
	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 FLEFKSARLP VKWMAPESLF EGIYTIKSDV WSYGILLWEI 850 860 870 880 890 900 FSLGVNPYPG IPVDANFYKL IQNGFKMDQP FYATEEIYII MQSCWAFDSR KRPSFPNLTS 910 920 930 940 950 FLGCQLADAE EAMYQNVDGR VSECPHTYQN RRPFSREMDL GLLSPQAQVE DS

References

	« Hide 'large scale' referencesShow '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. , 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. , 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, 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, MASS SPECTROMETRY.
[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, 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. , 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. , 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.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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.

IPI

IPI00945045.
IPI01010459.

PIR

A36873.
A39061.

RefSeq

NP_004110.2. NM_004119.2.

UniGene

Hs.507590.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1RJB	X-ray	2.10	A	564-958	[»]
3QS7	X-ray	4.30	E/F/G/H	27-436	[»]
3QS9	X-ray	7.80	E/F/G/H	27-540	[»]

DisProt

DP00312.

ProteinModelPortal

P36888.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-59769N.

IntAct

P36888. 1 interaction.

MINT

MINT-7103562.

STRING

9606.ENSP00000241453.

PTM databases

PhosphoSite

P36888.

Polymorphism databases

DMDM

156630887.

Proteomic databases

PaxDb

P36888.

PRIDE

P36888.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000241453; ENSP00000241453; ENSG00000122025.
ENST00000537084; ENSP00000438139; ENSG00000122025.

GeneID

2322.

KEGG

hsa:2322.

UCSC

uc001urw.3. human.
uc010tdn.2. human.

Organism-specific databases

CTD

2322.

GeneCards

GC13M028577.

H-InvDB

HIX0037338.

HGNC

HGNC:3765. FLT3.

HPA

CAB018358.

MIM

136351. gene.
601626. phenotype.

neXtProt

NX_P36888.

Orphanet

86851. Acute leukemia of ambiguous lineage.

PharmGKB

PA28181.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOVERGEN

HBG005735.

KO

K05092.

OrthoDB

EOG4FN4GX.

PhylomeDB

P36888.

Enzyme and pathway databases

BRENDA

2.7.10.1. 2681.

SignaLink

P36888.

Gene expression databases

ArrayExpress

P36888.

Bgee

P36888.

CleanEx

HS_FLT3.

Genevestigator

P36888.

GermOnline

ENSG00000122025. Homo sapiens.

Family and domain databases

Gene3D

2.60.40.10. 2 hits.

InterPro

IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR003599. Ig_sub.
IPR013151. Immunoglobulin.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_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]

Pfam

PF00047. ig. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]

PIRSF

PIRSF000615. TyrPK_CSF1-R. 1 hit.

SMART

SM00409. IG. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.

PROSITE

PS50835. 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]

ProtoNet

Search...

Other

BindingDB

P36888.

ChEMBL

CHEMBL1974.

DrugBank

DB00398. Sorafenib.
DB01268. Sunitinib.

EvolutionaryTrace

P36888.

GenomeRNAi

2322.

NextBio

9425.

SOURCE

Search...

Entry information

Entry name

FLT3_HUMAN

Accession

Primary (citable) accession number: P36888
Secondary accession number(s): A0AVG9 , B7ZLT7, B7ZLT8, F5H0A0, Q13414

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	August 21, 2007
Last modified:	May 29, 2013
This is version 136 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.