Q00342 (FLT3_MOUSE) 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
Tyrosine-protein kinase receptor flk-2
CD_antigen=CD135

Gene names

Name:	Flt3
Synonyms:	Flk-2, Flt-3

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	992 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.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 component	Endoplasmic reticulum Membrane
Disease	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	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	B cell differentiation Inferred from mutant phenotype PubMed 21228325. Source: UniProtKB common myeloid progenitor cell proliferation Inferred from mutant phenotype PubMed 21813452. Source: UniProtKB dendritic cell differentiation Inferred from mutant phenotype Ref.7. Source: UniProtKB leukocyte homeostasis Inferred from mutant phenotype Ref.7. Source: UniProtKB lymphocyte proliferation Inferred from mutant phenotype Ref.7. Source: UniProtKB 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 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_component	cell surface Inferred from direct assay PubMed 7630197PubMed 9620281. Source: MGI endoplasmic reticulum lumen Inferred from electronic annotation. Source: UniProtKB-SubCell integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	ATP 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: EC
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 27	27	Potential
	Chain	28 – 992	965	Receptor-type tyrosine-protein kinase FLT3		PRO_0000016779
Regions
	Topological domain	28 – 544	517	Extracellular Potential
	Transmembrane	545 – 564	20	Helical; Potential
	Topological domain	565 – 992	428	Cytoplasmic Potential
	Domain	254 – 344	91	Ig-like C2-type
	Domain	611 – 946	336	Protein kinase
	Nucleotide binding	617 – 625	9	ATP By similarity
	Region	592 – 598	7	Important 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 site	814	1	Proton acceptor By similarity
	Binding site	645	1	ATP By similarity
Amino acid modifications
	Modified residue	167	1	Phosphotyrosine By similarity
	Modified residue	402	1	Phosphotyrosine By similarity
	Modified residue	417	1	Phosphotyrosine By similarity
	Modified residue	575	1	Phosphoserine By similarity
	Modified residue	590	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	592	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	600	1	Phosphotyrosine By similarity
	Modified residue	727	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	729	1	Phosphothreonine By similarity
	Modified residue	760	1	Phosphoserine By similarity
	Modified residue	769	1	Phosphotyrosine By similarity
	Modified residue	796	1	Phosphotyrosine By similarity
	Modified residue	845	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	992	1	Phosphoserine By similarity
	Glycosylation	44	1	N-linked (GlcNAc...) Potential
	Glycosylation	133	1	N-linked (GlcNAc...) Potential
	Glycosylation	152	1	N-linked (GlcNAc...) Potential
	Glycosylation	307	1	N-linked (GlcNAc...) Potential
	Glycosylation	324	1	N-linked (GlcNAc...) Potential
	Glycosylation	352	1	N-linked (GlcNAc...) Potential
	Glycosylation	445	1	N-linked (GlcNAc...) Potential
	Glycosylation	474	1	N-linked (GlcNAc...) Potential
	Glycosylation	503	1	N-linked (GlcNAc...) Potential
	Glycosylation	542	1	N-linked (GlcNAc...) Potential
	Disulfide bond	36 ↔ 66		By similarity
	Disulfide bond	104 ↔ 115		By similarity
	Disulfide bond	200 ↔ 207		By similarity
	Disulfide bond	233 ↔ 242		By similarity
	Disulfide bond	273 ↔ 331		By similarity
	Disulfide bond	369 ↔ 408		By similarity
	Disulfide bond	382 ↔ 393		By similarity
Experimental info
	Mutagenesis	645	1	K → A: Loss of kinase activity; no effect on FIZ1-binding. Ref.6
	Sequence conflict	150	1	R → A in CAA42041. Ref.2
	Sequence conflict	242	1	C → S in CAA42041. Ref.2
	Sequence conflict	726	1	S → F in CAA42041. Ref.2
	Sequence conflict	957 – 979	23	CIRTS…GLRAQ → MYQNMGGNVPEHPSIYQNRR PLSREAGSEPP in CAA42041. Ref.2
	Sequence conflict	983	1	R → A in CAA42041. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Q00342 [UniParc]. Last modified April 1, 1993. Version 1. Checksum: 407A087853372100	FASTA	992	112,640
	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

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.
IPI	IPI00117909.
PIR	A39931. S18827.
RefSeq	NP_034359.2. NM_010229.2.
UniGene	Mm.194.
3D structure databases
ProteinModelPortal	Q00342.
SMR	Q00342. Positions 80-530, 573-950.
ModBase	Search...
PTM databases
PhosphoSite	Q00342.
Proteomic databases
PaxDb	Q00342.
PRIDE	Q00342.
Protocols and materials databases
DNASU	14255.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	14255.
KEGG	mmu:14255.
Organism-specific databases
CTD	2322.
MGI	MGI:95559. Flt3.
Phylogenomic databases
eggNOG	COG0515.
HOVERGEN	HBG005735.
InParanoid	Q00342.
KO	K05092.
OrthoDB	EOG4FN4GX.
Enzyme and pathway databases
BRENDA	2.7.10.1. 3474.
Gene expression databases
CleanEx	MM_FLT3.
Genevestigator	Q00342.
GermOnline	ENSMUSG00000042817. Mus musculus.
Family and domain databases
Gene3D	2.60.40.10. 1 hit.
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. 2 hits. 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
NextBio	285583.
SOURCE	Search...

Entry information

Entry name

FLT3_MOUSE

Accession

Primary (citable) accession number: Q00342

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	April 1, 1993
Last modified:	April 3, 2013
This is version 121 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program