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FLT3 (FMS-like tyrosine kinase 3)

Identity

Other namesCD135
FLK2 (Fetal liver kinase 2)
STK1 (Stem cell kinase 1)
HGNC (Hugo) FLT3
LocusID (NCBI) 2322
Location 13q12.2
Location_base_pair Starts at 28577411 and ends at 28674729 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description the FLT3 gene contains 24 exons and spans 96,982 bases (start:27,475,753 bp to end 27,572,735 from 13pter) oriented at the minus strand.
Transcription 3.7 kb; 2979 bp open reading frame

Protein

Description Size: 993 amino acids; 112804 Da;
FLT3 is a class III receptor tyrosine kinase (RTK) structurally related to the receptors for platelet derived growth factor (PDGF), colony stimulating factor 1 (CSF1), and KIT ligand (KL).; these RTK contain five immunoglobulin-like domains in the extracellular region and an intracelular tyrosine kinase domain splitted in two by a specific hydrophilic insertion (kinase insert); immunoprecipitation of the human FLT3 protein results in the appearance of a minor band of Mr 130 000 and a major band of Mr 155 000/160 000; the high-molecular-weight band corresponds to the mature, N-glycosylated form, and the low-molecular-weight band to the immature, high mannose-containing form; N-linked glycosylations account for 50 000 daltons.
Expression FLT3 expression was described on bone marrow CD34-positive cells, corresponding to multipotential, myeloid and B-lymphoid progenitor cells, and on monocytic cells; FLT3 expression is restricted to cells of the fetal liver expressing high levels of CD34; in addition, the FLT3 protein is expressed on blast cells from most ANLL and B-ALL.
Localisation Subcellular location: Type I membrane protein. 3D structure: PDB id 1RJB (3D).
Function FLT3 receptor function can be defined by the activity of its ligand (FL); FL is an early acting factor and supports the survival, proliferation and differentiation of primitive hemopoietic progenitor cells. Ligand binding to FLT3 promotes receptor dimerization and subsequent signalling through posphorylation of multiple cytoplasmatic proteins, including SHC, SHP-2, SHIP, Cbl, Cbl-b, Gab1 and Gab2, as well as the activation of several downstream signalling pathways, such as the Ras/Raf/MAPK and PI3 kinase cascades.
Function: Receptor for the FL cytokine. Has a tyrosine-protein kinase activity. Catalytic activity: ATP + a protein tyrosine = ADP + protein tyrosine phosphate.
Similarity: Belongs to the Tyr protein kinase family. CSF-1/PDGF receptor subfamily. Contains 1 immunoglobulin-like C2-type domain.
Homology Other tyrosine kinases: KIT, PDGFRA, PDGFRB, VEGFR

Mutations

Somatic Mutations in the FLT3 gene are the most frequent genetic aberration that have been described in acute myeloid leukemia. With 20-25% length mutations in the juxtamembrane domain are the most frequent, followed by 7-8% mutations in the second tyrosine kinase kinase domain, mostly point mutations in codon 835 or deletions of codon 836. Also point mutations in the juxta membrane domain have been described and the number of new mutations all over the total gene is still growing.

Implicated in

Entity FLT3-length mutation (FLT3-LM)
Disease Internal tandem duplications and/or insertions and, rarely, deletions in the FLT3-gene are implicated in 20-25% of all acute myeloid leukemias (AML). It was also described to be involved in 5-10 % myelodysplastic syndromes (MDS) refractory anaemia with excess of blasts (RAEB 1 and RAEB 2) and rare cases with acute lymphoblastic leukemia (ALL) The duplicated sequence belongs to exon 11 but sometimes involves intron 11 and exon 12. The most frequently used nomenclature is FLT3-ITD (internal tandem duplication). Because of the very heterogenous molecular structure the term FLT3-LM (length mutation) seems to be more adequate.
Prognosis An unfavourable impact on prognosis especially a high relapse rate of the FLT3-LM has been shown by many study groups. Patients with loss of the wildtype allele have an even worse prognosis than the mutated with retention of the wildtype allele. Perspective : It is of special interest that this mutation allows to perform PCR-based minimal residual disease detection in a high number of these high risk AML patients.
Cytogenetics FLT3-LM are highly correlated with a) normal karyotype, b) t(15;17)(q25;q21) c) t(6;9)(p23;q34)
Perspective: It is of special interest that this mutation allows to perform PCR-based minimal residual disease detection in a high number of these high risk AML patients.
Oncogenesis This mutation leads to constitutive ligand independent autophosphorylation of the receptor. The FLT3-LM vary in size and position in a nearly patient specific manner. Overall the aberrant structure of the juxtamembrane domain disrupts a negative regulatory domain, which leads to the constitutive receptor activation. Several Groups have reported qualitative differences in the intracellular signals provided by wild type and mutated receptors.Mutated receptor weakly works through MAP kinase and Akt but instead through strong and constitutively activated STAT5.
  
Entity FLT3 Tyrosine Kinase Domain Mutation (FLT3-TKD)
Disease In the second tyrosine kinase domain point mutations and small deletions mostly of codons 835 and 836, respectively, can be found in 7-8% of all AML.
Prognosis No independent impact on prognosis shown yet.
Cytogenetics In contrast to the FLT3-LM they do not seem to be specifically correlated to a certain AML type.
Oncogenesis These mutations also lead to constitutive autoactivation of the receptor. It has been suggested that TKD mutation may both trigger the activation loop and stabilize it in the active state.
  

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias 11q23ChildAMLID1615 11q23ID1030 11q23secondLeukID1131 t1119ELLID1029 t0812q24q22ID2057
t0814ID1050 8p11inMPDID1091 inv8p11q13ID1189 PrimarCutanALCLID2118 t0708q34p11ID1409

External links

Nomenclature
HGNC (Hugo)FLT3   3765
Cards
AtlasFLT3ID144
Entrez_Gene (NCBI)FLT3  2322  fms-related tyrosine kinase 3
GeneCards (Weizmann)FLT3
Ensembl (Hinxton)ENSG00000122025 [Gene_View]  chr13:28577411-28674729 [Contig_View]  FLT3 [Vega]
ICGC DataPortalENSG00000122025
cBioPortalFLT3
AceView (NCBI)FLT3
Genatlas (Paris)FLT3
WikiGenes2322
SOURCE (Princeton)NM_004119
Genomic and cartography
GoldenPath (UCSC)FLT3  -  13q12.2   chr13:28577411-28674729 -  13q12   [Description]    (hg19-Feb_2009)
EnsemblFLT3 - 13q12 [CytoView]
Mapping of homologs : NCBIFLT3 [Mapview]
OMIM136351   613065   
Gene and transcription
Genbank (Entrez)AW057705 BC036028 BC126350 BC144039 BC144040
RefSeq transcript (Entrez)NM_004119
RefSeq genomic (Entrez)AC_000145 NC_000013 NC_018924 NG_007066 NT_024524 NW_001838071 NW_004929388
Consensus coding sequences : CCDS (NCBI)FLT3
Cluster EST : UnigeneHs.507590 [ NCBI ]
CGAP (NCI)Hs.507590
Alternative Splicing : Fast-db (Paris)GSHG0008381
Alternative Splicing GalleryENSG00000122025
Gene ExpressionFLT3 [ NCBI-GEO ]     FLT3 [ SEEK ]   FLT3 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP36888 (Uniprot)
NextProtP36888  [Medical]
With graphics : InterProP36888
Splice isoforms : SwissVarP36888 (Swissvar)
Catalytic activity : Enzyme2.7.10.1 [ Enzyme-Expasy ]   2.7.10.12.7.10.1 [ IntEnz-EBI ]   2.7.10.1 [ BRENDA ]   2.7.10.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)IG_LIKE (PS50835)    PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)    RECEPTOR_TYR_KIN_III (PS00240)   
Domains : Interpro (EBI)Ig-like_dom [organisation]   Ig-like_fold [organisation]   Ig_sub [organisation]   Immunoglobulin [organisation]   Kinase-like_dom [organisation]   Prot_kinase_dom [organisation]   Protein_kinase_ATP_BS [organisation]   Ser-Thr/Tyr_kinase_cat_dom [organisation]   Tyr_kinase_AS [organisation]   Tyr_kinase_cat_dom [organisation]   Tyr_kinase_CSF1/PDGF_rcpt [organisation]   Tyr_kinase_rcpt_3_CS [organisation]  
Related proteins : CluSTrP36888
Domain families : Pfam (Sanger)ig (PF00047)    Pkinase_Tyr (PF07714)   
Domain families : Pfam (NCBI)pfam00047    pfam07714   
Domain families : Smart (EMBL)IG (SM00409)  TyrKc (SM00219)  
DMDM Disease mutations2322
Blocks (Seattle)P36888
PDB (SRS)1RJB    3QS7    3QS9   
PDB (PDBSum)1RJB    3QS7    3QS9   
PDB (IMB)1RJB    3QS7    3QS9   
PDB (RSDB)1RJB    3QS7    3QS9   
Human Protein AtlasENSG00000122025 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP36888
HPRD00635
IPIIPI01010459   IPI00945045   IPI00005722   
Protein Interaction databases
DIP (DOE-UCLA)P36888
IntAct (EBI)P36888
FunCoupENSG00000122025
BioGRIDFLT3
InParanoidP36888
Interologous Interaction database P36888
IntegromeDBFLT3
STRING (EMBL)FLT3
Ontologies - Pathways
Ontology : AmiGOleukocyte homeostasis  myeloid progenitor cell differentiation  pro-B cell differentiation  pro-T cell differentiation  transmembrane receptor protein tyrosine kinase activity  cytokine receptor activity  vascular endothelial growth factor-activated receptor activity  protein binding  ATP binding  endoplasmic reticulum lumen  integral component of plasma membrane  transmembrane receptor protein tyrosine kinase signaling pathway  positive regulation of cell proliferation  negative regulation of cell proliferation  cell surface  positive regulation of phosphatidylinositol 3-kinase signaling  peptidyl-tyrosine phosphorylation  cytokine-mediated signaling pathway  hemopoiesis  B cell differentiation  common myeloid progenitor cell proliferation  vascular endothelial growth factor signaling pathway  positive regulation of tyrosine phosphorylation of STAT protein  protein homodimerization activity  regulation of apoptotic process  positive regulation of MAP kinase activity  positive regulation of MAPK cascade  phosphatidylinositol 3-kinase binding  positive regulation of phosphatidylinositol 3-kinase activity  negative regulation of B cell differentiation  lymphocyte proliferation  protein autophosphorylation  cellular response to cytokine stimulus  cellular response to cytokine stimulus  dendritic cell differentiation  
Ontology : EGO-EBIleukocyte homeostasis  myeloid progenitor cell differentiation  pro-B cell differentiation  pro-T cell differentiation  transmembrane receptor protein tyrosine kinase activity  cytokine receptor activity  vascular endothelial growth factor-activated receptor activity  protein binding  ATP binding  endoplasmic reticulum lumen  integral component of plasma membrane  transmembrane receptor protein tyrosine kinase signaling pathway  positive regulation of cell proliferation  negative regulation of cell proliferation  cell surface  positive regulation of phosphatidylinositol 3-kinase signaling  peptidyl-tyrosine phosphorylation  cytokine-mediated signaling pathway  hemopoiesis  B cell differentiation  common myeloid progenitor cell proliferation  vascular endothelial growth factor signaling pathway  positive regulation of tyrosine phosphorylation of STAT protein  protein homodimerization activity  regulation of apoptotic process  positive regulation of MAP kinase activity  positive regulation of MAPK cascade  phosphatidylinositol 3-kinase binding  positive regulation of phosphatidylinositol 3-kinase activity  negative regulation of B cell differentiation  lymphocyte proliferation  protein autophosphorylation  cellular response to cytokine stimulus  cellular response to cytokine stimulus  dendritic cell differentiation  
Pathways : BIOCARTAErythrocyte Differentiation Pathway [Genes]   
Pathways : KEGGCytokine-cytokine receptor interaction    Hematopoietic cell lineage    Pathways in cancer    Transcriptional misregulation in cancer    Acute myeloid leukemia   
Protein Interaction DatabaseFLT3
Wikipedia pathwaysFLT3
Gene fusion - rearrangments
Rearrangement : TICdbETV6 [12p13.2]  -  FLT3 [17q21.31]
Rearrangement : TICdbSPTBN1 [2p16.2]  -  FLT3 [Xq28]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)FLT3
snp3D : Map Gene to Disease2322
SNP (GeneSNP Utah)FLT3
SNP : HGBaseFLT3
Genetic variants : HAPMAPFLT3
Exome VariantFLT3
1000_GenomesFLT3 
ICGC programENSG00000122025 
Cancer Gene: CensusFLT3 
Somatic Mutations in Cancer : COSMICFLT3 
CONAN: Copy Number AnalysisFLT3 
Mutations and Diseases : HGMDFLT3
Mutations and Diseases : intOGenFLT3
Genomic VariantsFLT3  FLT3 [DGVbeta]
dbVarFLT3
ClinVarFLT3
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM136351    613065   
MedgenFLT3
GENETestsFLT3
Disease Genetic AssociationFLT3
Huge Navigator FLT3 [HugePedia]  FLT3 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneFLT3
Homology/Alignments : Family Browser (UCSC)FLT3
Phylogenetic Trees/Animal Genes : TreeFamFLT3
Chemical/Protein Interactions : CTD2322
Chemical/Pharm GKB GenePA28181
Drug Sensitivity FLT3
Clinical trialFLT3
Cancer Resource (Charite)ENSG00000122025
Other databases
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=FLT3
Probes
Litterature
PubMed465 Pubmed reference(s) in Entrez
CoreMineFLT3
iHOPFLT3
OncoSearchFLT3

Bibliography

A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations.
Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR
Cell. 1991 ; 65 (7) : 1143-1152.
PMID 1648448
 
Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family.
Rosnet O, Marchetto S, deLapeyriere O, Birnbaum D
Oncogene. 1991 ; 6 (9) : 1641-1650.
PMID 1656368
 
Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages.
Birg F, Courcoul M, Rosnet O, Bardin F, Płębusque MJ, Marchetto S, Tabilio A, Mannoni P, Birnbaum D
Blood. 1992 ; 80 (10) : 2584-2593.
PMID 1384791
 
Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells.
Lyman SD, James L, Vanden Bos T, de Vries P, Brasel K, Gliniak B, Hollingsworth LT, Picha KS, McKenna HJ, Splett RR
Cell. 1993 ; 75 (6) : 1157-1167.
PMID 7505204
 
Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells.
Rosnet O, Schiff C, Płębusque MJ, Marchetto S, Tonnelle C, Toiron Y, Birg F, Birnbaum D
Blood. 1993 ; 82 (4) : 1110-1119.
PMID 8394751
 
Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs.
Hannum C, Culpepper J, Campbell D, McClanahan T, Zurawski S, Bazan JF, Kastelein R, Hudak S, Wagner J, Mattson J
Nature. 1994 ; 368 (6472) : 643-648.
PMID 8145851
 
Cellular and molecular characterization of the role of the flk-2/flt-3 receptor tyrosine kinase in hematopoietic stem cells.
Zeigler FC, Bennett BD, Jordan CT, Spencer SD, Baumhueter S, Carroll KJ, Hooley J, Bauer K, Matthews W
Blood. 1994 ; 84 (8) : 2422-2430.
PMID 7919361
 
Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors.
Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR
Immunity. 1995 ; 3 (1) : 147-161.
PMID 7621074
 
Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells.
Rosnet O, Bł║hring HJ, Marchetto S, Rappold I, Lavagna C, Sainty D, Arnoulet C, Chabannon C, Kanz L, Hannum C, Birnbaum D
Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 1996 ; 10 (2) : 238-248.
PMID 8637232
 
Flt3 ligand induces tumor regression and antitumor immune responses in vivo.
Lynch DH, Andreasen A, Maraskovsky E, Whitmore J, Miller RE, Schuh JC
Nature medicine. 1997 ; 3 (6) : 625-631.
PMID 9176488
 
Functional and phenotypic characterization of cord blood and bone marrow subsets expressing FLT3 (CD135) receptor tyrosine kinase.
Rappold I, Ziegler BL, KłĆhler I, Marchetto S, Rosnet O, Birnbaum D, Simmons PJ, Zannettino AC, Hill B, Neu S, Knapp W, Alitalo R, Alitalo K, Ullrich A, Kanz L, Bł║hring HJ
Blood. 1997 ; 90 (1) : 111-125.
PMID 9207445
 
c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities.
Lyman SD, Jacobsen SE
Blood. 1998 ; 91 (4) : 1101-1134.
PMID 9454740
 
Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia.
Kiyoi H, Naoe T, Nakano Y, Yokota S, Minami S, Miyawaki S, Asou N, Kuriyama K, Jinnai I, Shimazaki C, Akiyama H, Saito K, Oh H, Motoji T, Omoto E, Saito H, Ohno R, Ueda R
Blood. 1999 ; 93 (9) : 3074-3080.
PMID 10216104
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written05-1999Olivier Rosnet
Centre d'Immunologie INSERM-CNRS de Marseille-Luminy Case 906, 13288 Marseille Cedex 9, France
Updated06-2005Susanne Schnittger
MLL M├╝nchner Leuk├Ąmielabor GmbH, Max-Lebsche-Platz 31, 81377 M├╝nchen, Germany

Citation

This paper should be referenced as such :
Schnittger, S
FLT3 (FMS-like tyrosine kinase 3)
Atlas Genet Cytogenet Oncol Haematol. 2005;9(4):275-277.
Free online version   Free pdf version   [Bibliographic record ]
History of this paper:
Schnittger, S. FLT3 (FMS-like tyrosine kinase 3). Atlas Genet Cytogenet Oncol Haematol. 2005;9(4):275-277.
http://documents.irevues.inist.fr/bitstream/2042/38234/1/06-2005-FLT3ID144.pdf
URL : http://AtlasGeneticsOncology.org/Genes/FLT3ID144.html

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indexed on : Tue Sep 23 19:04:05 CEST 2014

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