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Q00342 (FLT3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 130. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·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
Tyrosine-protein kinase receptor flk-2
CD_antigen=CD135
Gene names
Name:Flt3
Synonyms:Flk-2, Flt-3
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length992 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.5 Ref.7 Ref.8 Ref.9 Ref.10

Catalytic activity

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.10

Enzyme regulation

Present in an inactive conformation in the absence of bound ligand. FLT3LG binding leads to dimerization and activation by autophosphorylation. Ref.10

Subunit structure

Monomer in the absence of bound FLT3LG. Homodimer in the presence of bound FLT3LG. Interacts with FIZ1 following ligand activation. Interacts with FES, FER, LYN, FGR, HCK, SRC and GRB2. Interacts with PTPRJ/DEP-1 and PTPN11/SHP2 By similarity. Ref.6

Subcellular location

Membrane; Single-pass type I membrane protein. Endoplasmic reticulum lumen By similarity. 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 By similarity.

Tissue specificity

Hematopoietic stem and progenitor cell-enriched populations. Found in brain, placenta and testis.

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 By similarity. Ref.10

Post-translational modification

N-glycosylated, contains complex N-glycans with sialic acid By similarity.

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 By similarity. Ref.10

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

Disruption phenotype

No visible phenotype. Mice are born at the expected Mendelian rate, develop normally and are fertile. They show normal blood cell counts, excepting reduced levels of primitive B-cell progenitors. Mice lacking both Flt3 and Kit show a reduction in both lymphoid and myeloid cell lineages. They appear normal, but are born at a lower frequency than expected and exhibit severely reduced viability after 3 weeks, none surviving more than six weeks. Ref.4

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
   DiseaseProto-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 termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processB cell differentiation

Inferred from mutant phenotype PubMed 21228325. Source: UniProtKB

cellular response to cytokine stimulus

Inferred from mutant phenotype Ref.7. Source: UniProtKB

common myeloid progenitor cell proliferation

Inferred from mutant phenotype PubMed 21813452. Source: UniProtKB

cytokine-mediated signaling pathway

Inferred from mutant phenotype Ref.7. Source: UniProtKB

dendritic cell differentiation

Inferred from mutant phenotype Ref.7. Source: UniProtKB

hemopoiesis

Inferred from sequence orthology PubMed 7507245. Source: MGI

leukocyte homeostasis

Inferred from mutant phenotype Ref.7. Source: UniProtKB

lymphocyte differentiation

Inferred from direct assay PubMed 12387740. Source: MGI

lymphocyte proliferation

Inferred from mutant phenotype Ref.7. Source: UniProtKB

lymphoid progenitor cell differentiation

Inferred from genetic interaction Ref.4. Source: MGI

myeloid progenitor cell differentiation

Inferred from mutant phenotype Ref.7. Source: UniProtKB

negative regulation of B cell differentiation

Inferred from direct assay PubMed 16618805. Source: MGI

negative regulation of cell proliferation

Inferred from mutant phenotype PubMed 7919361. Source: MGI

peptidyl-tyrosine phosphorylation

Inferred from direct assay Ref.3. Source: GOC

positive regulation of protein phosphorylation

Inferred from genetic interaction PubMed 20360400. Source: MGI

pro-B cell differentiation

Inferred from mutant phenotype PubMed 21228325. Source: UniProtKB

pro-T cell differentiation

Inferred from mutant phenotype Ref.4. Source: MGI

protein autophosphorylation

Inferred from direct assay PubMed 8183574Ref.3. Source: MGI

transmembrane receptor protein tyrosine kinase signaling pathway

Inferred from electronic annotation. Source: InterPro

   Cellular_componentcell surface

Inferred from direct assay PubMed 7630197PubMed 9620281. Source: MGI

endoplasmic reticulum lumen

Inferred from electronic annotation. Source: UniProtKB-SubCell

external side of plasma membrane

Inferred from direct assay PubMed 23528453. Source: MGI

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

cytokine receptor activity

Inferred from mutant phenotype Ref.7. Source: UniProtKB

phosphatidylinositol 3-kinase binding

Inferred from direct assay PubMed 8183574. Source: MGI

protein tyrosine kinase activity

Inferred from direct assay Ref.3. Source: MGI

transmembrane receptor protein tyrosine kinase activity

Inferred from electronic annotation. Source: UniProtKB-EC

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2727 Potential
Chain28 – 992965Receptor-type tyrosine-protein kinase FLT3
PRO_0000016779

Regions

Topological domain28 – 544517Extracellular Potential
Transmembrane545 – 56420Helical; Potential
Topological domain565 – 992428Cytoplasmic Potential
Domain254 – 34491Ig-like C2-type
Domain611 – 946336Protein kinase
Nucleotide binding617 – 6259ATP By similarity
Region592 – 5987Important for normal regulation of the kinase activity and for maintaining the kinase in an inactive state in the absence of ligand binding By similarity

Sites

Active site8141Proton acceptor By similarity
Binding site6451ATP By similarity

Amino acid modifications

Modified residue5731Phosphotyrosine By similarity
Modified residue5751Phosphoserine By similarity
Modified residue5901Phosphotyrosine; by autocatalysis By similarity
Modified residue5921Phosphotyrosine; by autocatalysis By similarity
Modified residue6001Phosphotyrosine By similarity
Modified residue7271Phosphotyrosine; by autocatalysis By similarity
Modified residue7601Phosphoserine By similarity
Modified residue7691Phosphotyrosine By similarity
Modified residue7961Phosphotyrosine By similarity
Modified residue8451Phosphotyrosine; by autocatalysis By similarity
Modified residue9921Phosphoserine By similarity
Glycosylation441N-linked (GlcNAc...) Potential
Glycosylation1331N-linked (GlcNAc...) Potential
Glycosylation1521N-linked (GlcNAc...) Potential
Glycosylation3071N-linked (GlcNAc...) Potential
Glycosylation3241N-linked (GlcNAc...) Potential
Glycosylation3521N-linked (GlcNAc...) Potential
Glycosylation4451N-linked (GlcNAc...) Potential
Glycosylation4741N-linked (GlcNAc...) Potential
Glycosylation5031N-linked (GlcNAc...) Potential
Glycosylation5421N-linked (GlcNAc...) Potential
Disulfide bond36 ↔ 66 By similarity
Disulfide bond104 ↔ 115 By similarity
Disulfide bond200 ↔ 207 By similarity
Disulfide bond233 ↔ 242 By similarity
Disulfide bond273 ↔ 331 By similarity
Disulfide bond369 ↔ 408 By similarity
Disulfide bond382 ↔ 393 By similarity

Experimental info

Mutagenesis6451K → A: Loss of kinase activity; no effect on FIZ1-binding. Ref.6
Sequence conflict1501R → A in CAA42041. Ref.2
Sequence conflict2421C → S in CAA42041. Ref.2
Sequence conflict7261S → F in CAA42041. Ref.2
Sequence conflict957 – 97923CIRTS…GLRAQ → MYQNMGGNVPEHPSIYQNRR PLSREAGSEPP in CAA42041. Ref.2
Sequence conflict9831R → A in CAA42041. Ref.2

Sequences

Sequence LengthMass (Da)Tools
Q00342 [UniParc].

Last modified April 1, 1993. Version 1.
Checksum: 407A087853372100

FASTA992112,640
        10         20         30         40         50         60 
MRALAQRSDR RLLLLVVLSV MILETVTNQD LPVIKCVLIS HENNGSSAGK PSSYRMVRGS 

        70         80         90        100        110        120 
PEDLQCTPRR QSEGTVYEAA TVEVAESGSI TLQVQLATPG DLSCLWVFKH SSLGCQPHFD 

       130        140        150        160        170        180 
LQNRGIVSMA ILNVTETQAG EYLLHIQSER ANYTVLFTVN VRDTQLYVLR RPYFRKMENQ 

       190        200        210        220        230        240 
DALLCISEGV PEPTVEWVLC SSHRESCKEE GPAVVRKEEK VLHELFGTDI RCCARNALGR 

       250        260        270        280        290        300 
ECTKLFTIDL NQAPQSTLPQ LFLKVGEPLW IRCKAIHVNH GFGLTWELED KALEEGSYFE 

       310        320        330        340        350        360 
MSTYSTNRTM IRILLAFVSS VGRNDTGYYT CSSSKHPSQS ALVTILEKGF INATSSQEEY 

       370        380        390        400        410        420 
EIDPYEKFCF SVRFKAYPRI RCTWIFSQAS FPCEQRGLED GYSISKFCDH KNKPGEYIFY 

       430        440        450        460        470        480 
AENDDAQFTK MFTLNIRKKP QVLANASASQ ASCSSDGYPL PSWTWKKCSD KSPNCTEEIP 

       490        500        510        520        530        540 
EGVWNKKANR KVFGQWVSSS TLNMSEAGKG LLVKCCAYNS MGTSCETIFL NSPGPFPFIQ 

       550        560        570        580        590        600 
DNISFYATIG LCLPFIVVLI VLICHKYKKQ FRYESQLQMI QVTGPLDNEY FYVDFRDYEY 

       610        620        630        640        650        660 
DLKWEFPREN LEFGKVLGSG AFGRVMNATA YGISKTGVSI QVAVKMLKEK ADSCEKEALM 

       670        680        690        700        710        720 
SELKMMTHLG HHDNIVNLLG ACTLSGPVYL IFEYCCYGDL LNYLRSKREK FHRTWTEIFK 

       730        740        750        760        770        780 
EHNFSSYPTF QAHSNSSMPG SREVQLHPPL DQLSGFNGNS IHSEDEIEYE NQKRLAEEEE 

       790        800        810        820        830        840 
EDLNVLTFED LLCFAYQVAK GMEFLEFKSC VHRDLAARNV LVTHGKVVKI CDFGLARDIL 

       850        860        870        880        890        900 
SDSSYVVRGN ARLPVKWMAP ESLFEGIYTI KSDVWSYGIL LWEIFSLGVN PYPGIPVDAN 

       910        920        930        940        950        960 
FYKLIQSGFK MEQPFYATEG IYFVMQSCWA FDSRKRPSFP NLTSFLGCQL AEAEEACIRT 

       970        980        990 
SIHLPKQAAP QQRGGLRAQS PQRQVKIHRE RS 

« Hide

References

[1]"A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations."
Matthews W., Jordan C.T., Wiegand G.W., Pardoll D., Lemischka I.R.
Cell 65:1143-1152(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Liver.
[2]"Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family."
Rosnet O., Marchetto S., Delapeyriere O., Birnbaum D.
Oncogene 6:1641-1650(1991) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]"Biochemical characterization and analysis of the transforming potential of the FLT3/FLK2 receptor tyrosine kinase."
Maroc N., Rottapel R., Rosnet O., Marchetto S., Lavezzi C., Mannoni P., Birnbaum D., Dubreuil P.
Oncogene 8:909-918(1993) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION.
[4]"Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors."
Mackarehtschian K., Hardin J.D., Moore K.A., Boast S., Goff S.P., Lemischka I.R.
Immunity 3:147-161(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE.
[5]"Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified."
Maraskovsky E., Brasel K., Teepe M., Roux E.R., Lyman S.D., Shortman K., McKenna H.J.
J. Exp. Med. 184:1953-1962(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN REGULATION OF DENDRITIC CELL DEVELOPMENT.
[6]"Fiz1, a novel zinc finger protein interacting with the receptor tyrosine kinase Flt3."
Wolf I., Rohrschneider L.R.
J. Biol. Chem. 274:21478-21484(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH FIZ1, MUTAGENESIS OF LYS-645.
[7]"The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues."
Waskow C., Liu K., Darrasse-Jeze G., Guermonprez P., Ginhoux F., Merad M., Shengelia T., Yao K., Nussenzweig M.
Nat. Immunol. 9:676-683(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[8]"In vivo analysis of dendritic cell development and homeostasis."
Liu K., Victora G.D., Schwickert T.A., Guermonprez P., Meredith M.M., Yao K., Chu F.F., Randolph G.J., Rudensky A.Y., Nussenzweig M.
Science 324:392-397(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[9]"Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells."
Eidenschenk C., Crozat K., Krebs P., Arens R., Popkin D., Arnold C.N., Blasius A.L., Benedict C.A., Moresco E.M., Xia Y., Beutler B.
Proc. Natl. Acad. Sci. U.S.A. 107:9759-9764(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN REGULATION OF DENDRITIC CELL DEVELOPMENT.
[10]"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, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, DOMAIN, ENZYME REGULATION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M64689 mRNA. Translation: AAA37634.1.
X59398 mRNA. Translation: CAA42041.1.
PIRA39931.
S18827.
RefSeqNP_034359.2. NM_010229.2.
UniGeneMm.194.

3D structure databases

ProteinModelPortalQ00342.
SMRQ00342. Positions 80-530, 573-953.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid199707. 4 interactions.
MINTMINT-85239.

Chemistry

ChEMBLCHEMBL2034796.

PTM databases

PhosphoSiteQ00342.

Proteomic databases

PaxDbQ00342.
PRIDEQ00342.

Protocols and materials databases

DNASU14255.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID14255.
KEGGmmu:14255.

Organism-specific databases

CTD2322.
MGIMGI:95559. Flt3.

Phylogenomic databases

eggNOGCOG0515.
HOVERGENHBG005735.
InParanoidQ00342.
KOK05092.

Enzyme and pathway databases

BRENDA2.7.10.1. 3474.

Gene expression databases

CleanExMM_FLT3.
GenevestigatorQ00342.

Family and domain databases

Gene3D2.60.40.10. 1 hit.
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. 2 hits.
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

NextBio285583.
PROQ00342.
SOURCESearch...

Entry information

Entry nameFLT3_MOUSE
AccessionPrimary (citable) accession number: Q00342
Entry history
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: April 1, 1993
Last modified: April 16, 2014
This is version 130 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot