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Protein

Receptor-type tyrosine-protein kinase FLT3

Gene

Flt3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.5 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation1 Publication

Enzyme regulationi

Present in an inactive conformation in the absence of bound ligand. FLT3LG binding leads to dimerization and activation by autophosphorylation.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei645ATPPROSITE-ProRule annotation1
Active sitei814Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi617 – 625ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • cytokine receptor activity Source: UniProtKB
  • phosphatidylinositol 3-kinase binding Source: MGI
  • protein tyrosine kinase activity Source: MGI
  • transmembrane receptor protein tyrosine kinase activity Source: UniProtKB-EC
  • ubiquitin protein ligase binding Source: UniProtKB

GO - Biological processi

  • antigen processing and presentation Source: MGI
  • B cell differentiation Source: UniProtKB
  • cellular response to cytokine stimulus Source: UniProtKB
  • cellular response to virus Source: MGI
  • common myeloid progenitor cell proliferation Source: UniProtKB
  • cytokine-mediated signaling pathway Source: UniProtKB
  • dendritic cell differentiation Source: UniProtKB
  • dendritic cell homeostasis Source: MGI
  • hemopoiesis Source: MGI
  • homeostasis of number of cells within a tissue Source: MGI
  • leukocyte homeostasis Source: UniProtKB
  • lymph node development Source: MGI
  • lymphocyte differentiation Source: MGI
  • lymphocyte proliferation Source: UniProtKB
  • lymphoid progenitor cell differentiation Source: MGI
  • myeloid progenitor cell differentiation Source: UniProtKB
  • negative regulation of B cell differentiation Source: MGI
  • negative regulation of cell proliferation Source: MGI
  • negative regulation of interleukin-6 production Source: MGI
  • negative regulation of tumor necrosis factor production Source: MGI
  • positive regulation of interferon-alpha production Source: MGI
  • positive regulation of interferon-alpha secretion Source: MGI
  • positive regulation of interferon-gamma production Source: MGI
  • positive regulation of interferon-gamma secretion Source: MGI
  • positive regulation of interleukin-12 production Source: MGI
  • positive regulation of interleukin-12 secretion Source: MGI
  • positive regulation of multicellular organism growth Source: MGI
  • positive regulation of protein phosphorylation Source: MGI
  • post-embryonic development Source: MGI
  • pro-B cell differentiation Source: UniProtKB
  • pro-T cell differentiation Source: MGI
  • protein autophosphorylation Source: MGI
  • spleen development Source: MGI
  • transmembrane receptor protein tyrosine kinase signaling pathway Source: InterPro
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.

Names & Taxonomyi

Protein namesi
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
Tyrosine-protein kinase receptor flk-2
CD_antigen: CD135
Gene namesi
Name:Flt3
Synonyms:Flk-2, Flt-3
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:95559. Flt3.

Subcellular locationi

  • 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).By similarity

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini28 – 544ExtracellularSequence analysisAdd BLAST517
Transmembranei545 – 564HelicalSequence analysisAdd BLAST20
Topological domaini565 – 992CytoplasmicSequence analysisAdd BLAST428

GO - Cellular componenti

  • cell surface Source: MGI
  • endoplasmic reticulum lumen Source: UniProtKB-SubCell
  • external side of plasma membrane Source: MGI
  • integral component of membrane Source: UniProtKB-KW
Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Disruption phenotypei

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.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi645K → A: Loss of kinase activity; no effect on FIZ1-binding. 1 Publication1

Keywords - Diseasei

Proto-oncogene

Chemistry databases

ChEMBLiCHEMBL2034796.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 27Sequence analysisAdd BLAST27
ChainiPRO_000001677928 – 1000Receptor-type tyrosine-protein kinase FLT3Add BLAST973

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi36 ↔ 66PROSITE-ProRule annotation
Glycosylationi44N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi104 ↔ 115PROSITE-ProRule annotation
Glycosylationi133N-linked (GlcNAc...)Sequence analysis1
Glycosylationi152N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi200 ↔ 207PROSITE-ProRule annotation
Disulfide bondi273 ↔ 331PROSITE-ProRule annotation
Glycosylationi307N-linked (GlcNAc...)Sequence analysis1
Glycosylationi324N-linked (GlcNAc...)Sequence analysis1
Glycosylationi352N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi369 ↔ 408PROSITE-ProRule annotation
Disulfide bondi382 ↔ 393PROSITE-ProRule annotation
Glycosylationi445N-linked (GlcNAc...)Sequence analysis1
Glycosylationi474N-linked (GlcNAc...)Sequence analysis1
Glycosylationi503N-linked (GlcNAc...)Sequence analysis1
Glycosylationi542N-linked (GlcNAc...)Sequence analysis1
Modified residuei573PhosphotyrosineBy similarity1
Modified residuei575PhosphoserineBy similarity1
Modified residuei590Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei592Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei600PhosphotyrosineBy similarity1
Modified residuei727Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei760PhosphoserineBy similarity1
Modified residuei769PhosphotyrosineBy similarity1
Modified residuei796PhosphotyrosineBy similarity1
Modified residuei845Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei958PhosphotyrosineBy similarity1
Modified residuei972PhosphotyrosineBy similarity1
Modified residuei1000PhosphoserineBy similarity1

Post-translational modificationi

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

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ00342.
PRIDEiQ00342.

PTM databases

iPTMnetiQ00342.
PhosphoSitePlusiQ00342.

Expressioni

Tissue specificityi

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

Gene expression databases

CleanExiMM_FLT3.

Interactioni

Subunit structurei

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). Interacts with RNF115 and RNF126.By similarity1 Publication

GO - Molecular functioni

  • phosphatidylinositol 3-kinase binding Source: MGI
  • ubiquitin protein ligase binding Source: UniProtKB

Protein-protein interaction databases

BioGridi199707. 3 interactors.
MINTiMINT-85239.
STRINGi10090.ENSMUSP00000039041.

Chemistry databases

BindingDBiQ00342.

Structurei

3D structure databases

ProteinModelPortaliQ00342.
SMRiQ00342.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini254 – 344Ig-like C2-typeAdd BLAST91
Domaini611 – 946Protein kinasePROSITE-ProRule annotationAdd BLAST336

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni592 – 598Important for normal regulation of the kinase activity and for maintaining the kinase in an inactive state in the absence of ligand bindingBy similarity7

Domaini

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).By similarity

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Immunoglobulin domain, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0200. Eukaryota.
COG0515. LUCA.
HOVERGENiHBG005735.
InParanoidiQ00342.
KOiK05092.

Family and domain databases

Gene3Di2.60.40.10. 2 hits.
InterProiIPR030118. FLT3.
IPR007110. 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.
IPR001824. Tyr_kinase_rcpt_3_CS.
[Graphical view]
PANTHERiPTHR24416:SF356. PTHR24416:SF356. 2 hits.
PfamiPF00047. ig. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
SMARTiSM00409. IG. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF48726. SSF48726. 2 hits.
SSF56112. SSF56112. 2 hits.
PROSITEiPS50835. 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]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q00342-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MRALAQRSDR RLLLLVVLSV MILETVTNQD LPVIKCVLIS HENNGSSAGK
60 70 80 90 100
PSSYRMVRGS PEDLQCTPRR QSEGTVYEAA TVEVAESGSI TLQVQLATPG
110 120 130 140 150
DLSCLWVFKH SSLGCQPHFD LQNRGIVSMA ILNVTETQAG EYLLHIQSEA
160 170 180 190 200
ANYTVLFTVN VRDTQLYVLR RPYFRKMENQ DALLCISEGV PEPTVEWVLC
210 220 230 240 250
SSHRESCKEE GPAVVRKEEK VLHELFGTDI RCCARNALGR ESTKLFTIDL
260 270 280 290 300
NQAPQSTLPQ LFLKVGEPLW IRCKAIHVNH GFGLTWELED KALEEGSYFE
310 320 330 340 350
MSTYSTNRTM IRILLAFVSS VGRNDTGYYT CSSSKHPSQS ALVTILEKGF
360 370 380 390 400
INATSSQEEY EIDPYEKFCF SVRFKAYPRI RCTWIFSQAS FPCEQRGLED
410 420 430 440 450
GYSISKFCDH KNKPGEYIFY AENDDAQFTK MFTLNIRKKP QVLANASASQ
460 470 480 490 500
ASCSSDGYPL PSWTWKKCSD KSPNCTEEIP EGVWNKKANR KVFGQWVSSS
510 520 530 540 550
TLNMSEAGKG LLVKCCAYNS MGTSCETIFL NSPGPFPFIQ DNISFYATIG
560 570 580 590 600
LCLPFIVVLI VLICHKYKKQ FRYESQLQMI QVTGPLDNEY FYVDFRDYEY
610 620 630 640 650
DLKWEFPREN LEFGKVLGSG AFGRVMNATA YGISKTGVSI QVAVKMLKEK
660 670 680 690 700
ADSCEKEALM SELKMMTHLG HHDNIVNLLG ACTLSGPVYL IFEYCCYGDL
710 720 730 740 750
LNYLRSKREK FHRTWTEIFK EHNFSFYPTF QAHSNSSMPG SREVQLHPPL
760 770 780 790 800
DQLSGFNGNS IHSEDEIEYE NQKRLAEEEE EDLNVLTFED LLCFAYQVAK
810 820 830 840 850
GMEFLEFKSC VHRDLAARNV LVTHGKVVKI CDFGLARDIL SDSSYVVRGN
860 870 880 890 900
ARLPVKWMAP ESLFEGIYTI KSDVWSYGIL LWEIFSLGVN PYPGIPVDAN
910 920 930 940 950
FYKLIQSGFK MEQPFYATEG IYFVMQSCWA FDSRKRPSFP NLTSFLGCQL
960 970 980 990 1000
AEAEEAMYQN MGGNVPEHPS IYQNRRPLSR EAGSEPPSPQ AQVKIHRERS
Length:1,000
Mass (Da):113,496
Last modified:April 1, 2015 - v2
Checksum:iE67CA9526D7DEE2F
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti150A → R in AAA37634 (PubMed:1648448).Curated1
Sequence conflicti242S → C in AAA37634 (PubMed:1648448).Curated1
Sequence conflicti726F → S in AAA37634 (PubMed:1648448).Curated1
Sequence conflicti957 – 991MYQNM…PSPQA → CIRTSIHLPKQAAPQQRGGL RAQSPQR in AAA37634 (PubMed:1648448).CuratedAdd BLAST35

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M64689 mRNA. Translation: AAA37634.1.
X59398 mRNA. Translation: CAA42041.1.
CCDSiCCDS39400.1.
PIRiA39931.
S18827.
RefSeqiNP_034359.2. NM_010229.2.
UniGeneiMm.194.

Genome annotation databases

GeneIDi14255.
KEGGimmu:14255.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M64689 mRNA. Translation: AAA37634.1.
X59398 mRNA. Translation: CAA42041.1.
CCDSiCCDS39400.1.
PIRiA39931.
S18827.
RefSeqiNP_034359.2. NM_010229.2.
UniGeneiMm.194.

3D structure databases

ProteinModelPortaliQ00342.
SMRiQ00342.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi199707. 3 interactors.
MINTiMINT-85239.
STRINGi10090.ENSMUSP00000039041.

Chemistry databases

BindingDBiQ00342.
ChEMBLiCHEMBL2034796.

PTM databases

iPTMnetiQ00342.
PhosphoSitePlusiQ00342.

Proteomic databases

PaxDbiQ00342.
PRIDEiQ00342.

Protocols and materials databases

DNASUi14255.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi14255.
KEGGimmu:14255.

Organism-specific databases

CTDi2322.
MGIiMGI:95559. Flt3.

Phylogenomic databases

eggNOGiKOG0200. Eukaryota.
COG0515. LUCA.
HOVERGENiHBG005735.
InParanoidiQ00342.
KOiK05092.

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.

Miscellaneous databases

PROiQ00342.
SOURCEiSearch...

Gene expression databases

CleanExiMM_FLT3.

Family and domain databases

Gene3Di2.60.40.10. 2 hits.
InterProiIPR030118. FLT3.
IPR007110. 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.
IPR001824. Tyr_kinase_rcpt_3_CS.
[Graphical view]
PANTHERiPTHR24416:SF356. PTHR24416:SF356. 2 hits.
PfamiPF00047. ig. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
SMARTiSM00409. IG. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF48726. SSF48726. 2 hits.
SSF56112. SSF56112. 2 hits.
PROSITEiPS50835. 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]
ProtoNetiSearch...

Entry informationi

Entry nameiFLT3_MOUSE
AccessioniPrimary (citable) accession number: Q00342
Entry historyi
Integrated into UniProtKB/Swiss-Prot: April 1, 1993
Last sequence update: April 1, 2015
Last modified: November 2, 2016
This is version 150 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.