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Q00342

- FLT3_MOUSE

UniProt

Q00342 - FLT3_MOUSE

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Protein

Receptor-type tyrosine-protein kinase FLT3

Gene
Flt3, Flk-2, Flt-3
Organism
Mus musculus (Mouse)
Status
Reviewed - 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.1 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)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei645 – 6451ATP By similarity
Active sitei814 – 8141Proton acceptor By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi617 – 6259ATP By similarity

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. cytokine receptor activity Source: UniProtKB
  3. phosphatidylinositol 3-kinase binding Source: MGI
  4. protein binding Source: UniProtKB
  5. protein tyrosine kinase activity Source: MGI
  6. transmembrane receptor protein tyrosine kinase activity Source: UniProtKB-EC

GO - Biological processi

  1. B cell differentiation Source: UniProtKB
  2. cellular response to cytokine stimulus Source: UniProtKB
  3. common myeloid progenitor cell proliferation Source: UniProtKB
  4. cytokine-mediated signaling pathway Source: UniProtKB
  5. dendritic cell differentiation Source: UniProtKB
  6. hemopoiesis Source: MGI
  7. leukocyte homeostasis Source: UniProtKB
  8. lymphocyte differentiation Source: MGI
  9. lymphocyte proliferation Source: UniProtKB
  10. lymphoid progenitor cell differentiation Source: MGI
  11. myeloid progenitor cell differentiation Source: UniProtKB
  12. negative regulation of B cell differentiation Source: MGI
  13. negative regulation of cell proliferation Source: MGI
  14. peptidyl-tyrosine phosphorylation Source: GOC
  15. positive regulation of protein phosphorylation Source: MGI
  16. pro-B cell differentiation Source: UniProtKB
  17. pro-T cell differentiation Source: MGI
  18. protein autophosphorylation Source: MGI
  19. 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
ProteomesiUP000000589: 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.

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini28 – 544517Extracellular Reviewed predictionAdd
BLAST
Transmembranei545 – 56420Helical; Reviewed predictionAdd
BLAST
Topological domaini565 – 992428Cytoplasmic Reviewed predictionAdd
BLAST

GO - Cellular componenti

  1. cell surface Source: MGI
  2. endoplasmic reticulum lumen Source: UniProtKB-SubCell
  3. external side of plasma membrane Source: MGI
  4. 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)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi645 – 6451K → A: Loss of kinase activity; no effect on FIZ1-binding. 1 Publication

Keywords - Diseasei

Proto-oncogene

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2727 Reviewed predictionAdd
BLAST
Chaini28 – 992965Receptor-type tyrosine-protein kinase FLT3PRO_0000016779Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi36 ↔ 66 By similarity
Glycosylationi44 – 441N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi104 ↔ 115 By similarity
Glycosylationi133 – 1331N-linked (GlcNAc...) Reviewed prediction
Glycosylationi152 – 1521N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi200 ↔ 207 By similarity
Disulfide bondi233 ↔ 242 By similarity
Disulfide bondi273 ↔ 331 By similarity
Glycosylationi307 – 3071N-linked (GlcNAc...) Reviewed prediction
Glycosylationi324 – 3241N-linked (GlcNAc...) Reviewed prediction
Glycosylationi352 – 3521N-linked (GlcNAc...) Reviewed prediction
Disulfide bondi369 ↔ 408 By similarity
Disulfide bondi382 ↔ 393 By similarity
Glycosylationi445 – 4451N-linked (GlcNAc...) Reviewed prediction
Glycosylationi474 – 4741N-linked (GlcNAc...) Reviewed prediction
Glycosylationi503 – 5031N-linked (GlcNAc...) Reviewed prediction
Glycosylationi542 – 5421N-linked (GlcNAc...) Reviewed prediction
Modified residuei573 – 5731Phosphotyrosine By similarity
Modified residuei575 – 5751Phosphoserine By similarity
Modified residuei590 – 5901Phosphotyrosine; by autocatalysis By similarity
Modified residuei592 – 5921Phosphotyrosine; by autocatalysis By similarity
Modified residuei600 – 6001Phosphotyrosine By similarity
Modified residuei727 – 7271Phosphotyrosine; by autocatalysis By similarity
Modified residuei760 – 7601Phosphoserine By similarity
Modified residuei769 – 7691Phosphotyrosine By similarity
Modified residuei796 – 7961Phosphotyrosine By similarity
Modified residuei845 – 8451Phosphotyrosine; by autocatalysis By similarity
Modified residuei992 – 9921Phosphoserine By similarity

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.1 Publication
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

PhosphoSiteiQ00342.

Expressioni

Tissue specificityi

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

Gene expression databases

CleanExiMM_FLT3.
GenevestigatoriQ00342.

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.1 Publication

Protein-protein interaction databases

BioGridi199707. 4 interactions.
MINTiMINT-85239.

Structurei

3D structure databases

ProteinModelPortaliQ00342.
SMRiQ00342. Positions 80-530, 573-953.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini254 – 34491Ig-like C2-typeAdd
BLAST
Domaini611 – 946336Protein kinaseAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni592 – 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

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.1 Publication

Sequence similaritiesi

Keywords - Domaini

Immunoglobulin domain, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0515.
HOVERGENiHBG005735.
InParanoidiQ00342.
KOiK05092.

Family and domain databases

Gene3Di2.60.40.10. 1 hit.
InterProiIPR007110. 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]
PfamiPF00047. ig. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
PIRSFiPIRSF000615. TyrPK_CSF1-R. 1 hit.
SMARTiSM00409. IG. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. 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

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MRALAQRSDR RLLLLVVLSV MILETVTNQD LPVIKCVLIS HENNGSSAGK    50
PSSYRMVRGS PEDLQCTPRR QSEGTVYEAA TVEVAESGSI TLQVQLATPG 100
DLSCLWVFKH SSLGCQPHFD LQNRGIVSMA ILNVTETQAG EYLLHIQSER 150
ANYTVLFTVN VRDTQLYVLR RPYFRKMENQ DALLCISEGV PEPTVEWVLC 200
SSHRESCKEE GPAVVRKEEK VLHELFGTDI RCCARNALGR ECTKLFTIDL 250
NQAPQSTLPQ LFLKVGEPLW IRCKAIHVNH GFGLTWELED KALEEGSYFE 300
MSTYSTNRTM IRILLAFVSS VGRNDTGYYT CSSSKHPSQS ALVTILEKGF 350
INATSSQEEY EIDPYEKFCF SVRFKAYPRI RCTWIFSQAS FPCEQRGLED 400
GYSISKFCDH KNKPGEYIFY AENDDAQFTK MFTLNIRKKP QVLANASASQ 450
ASCSSDGYPL PSWTWKKCSD KSPNCTEEIP EGVWNKKANR KVFGQWVSSS 500
TLNMSEAGKG LLVKCCAYNS MGTSCETIFL NSPGPFPFIQ DNISFYATIG 550
LCLPFIVVLI VLICHKYKKQ FRYESQLQMI QVTGPLDNEY FYVDFRDYEY 600
DLKWEFPREN LEFGKVLGSG AFGRVMNATA YGISKTGVSI QVAVKMLKEK 650
ADSCEKEALM SELKMMTHLG HHDNIVNLLG ACTLSGPVYL IFEYCCYGDL 700
LNYLRSKREK FHRTWTEIFK EHNFSSYPTF QAHSNSSMPG SREVQLHPPL 750
DQLSGFNGNS IHSEDEIEYE NQKRLAEEEE EDLNVLTFED LLCFAYQVAK 800
GMEFLEFKSC VHRDLAARNV LVTHGKVVKI CDFGLARDIL SDSSYVVRGN 850
ARLPVKWMAP ESLFEGIYTI KSDVWSYGIL LWEIFSLGVN PYPGIPVDAN 900
FYKLIQSGFK MEQPFYATEG IYFVMQSCWA FDSRKRPSFP NLTSFLGCQL 950
AEAEEACIRT SIHLPKQAAP QQRGGLRAQS PQRQVKIHRE RS 992
Length:992
Mass (Da):112,640
Last modified:April 1, 1993 - v1
Checksum:i407A087853372100
GO

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti150 – 1501R → A in CAA42041. 1 Publication
Sequence conflicti242 – 2421C → S in CAA42041. 1 Publication
Sequence conflicti726 – 7261S → F in CAA42041. 1 Publication
Sequence conflicti957 – 97923CIRTS…GLRAQ → MYQNMGGNVPEHPSIYQNRR PLSREAGSEPP in CAA42041. 1 PublicationAdd
BLAST
Sequence conflicti983 – 9831R → A in CAA42041. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
M64689 mRNA. Translation: AAA37634.1.
X59398 mRNA. Translation: CAA42041.1.
PIRiA39931.
S18827.
RefSeqiNP_034359.2. NM_010229.2.
UniGeneiMm.194.

Genome annotation databases

GeneIDi14255.
KEGGimmu:14255.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
M64689 mRNA. Translation: AAA37634.1 .
X59398 mRNA. Translation: CAA42041.1 .
PIRi A39931.
S18827.
RefSeqi NP_034359.2. NM_010229.2.
UniGenei Mm.194.

3D structure databases

ProteinModelPortali Q00342.
SMRi Q00342. Positions 80-530, 573-953.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 199707. 4 interactions.
MINTi MINT-85239.

Chemistry

ChEMBLi CHEMBL2034796.

PTM databases

PhosphoSitei Q00342.

Proteomic databases

PaxDbi Q00342.
PRIDEi Q00342.

Protocols and materials databases

DNASUi 14255.
Structural Biology Knowledgebase Search...

Genome annotation databases

GeneIDi 14255.
KEGGi mmu:14255.

Organism-specific databases

CTDi 2322.
MGIi MGI:95559. Flt3.

Phylogenomic databases

eggNOGi COG0515.
HOVERGENi HBG005735.
InParanoidi Q00342.
KOi K05092.

Enzyme and pathway databases

BRENDAi 2.7.10.1. 3474.

Miscellaneous databases

NextBioi 285583.
PROi Q00342.
SOURCEi Search...

Gene expression databases

CleanExi MM_FLT3.
Genevestigatori Q00342.

Family and domain databases

Gene3Di 2.60.40.10. 1 hit.
InterProi 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.
IPR016243. Tyr_kinase_CSF1/PDGF_rcpt.
IPR001824. Tyr_kinase_rcpt_3_CS.
[Graphical view ]
Pfami PF00047. ig. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view ]
PIRSFi PIRSF000615. TyrPK_CSF1-R. 1 hit.
SMARTi SM00409. IG. 2 hits.
SM00219. TyrKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 2 hits.
PROSITEi 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 ]
ProtoNeti Search...

Publicationsi

  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. 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.

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, 1993
Last modified: June 11, 2014
This is version 131 of the entry and version 1 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

External Data

Dasty 3

Similar proteinsi