Description: Homo sapiens fms-related tyrosine kinase 3 (FLT3), mRNA. RefSeq Summary (NM_004119): This gene encodes a class III receptor tyrosine kinase that regulates hematopoiesis. This receptor is activated by binding of the fms-related tyrosine kinase 3 ligand to the extracellular domain, which induces homodimer formation in the plasma membrane leading to autophosphorylation of the receptor. The activated receptor kinase subsequently phosphorylates and activates multiple cytoplasmic effector molecules in pathways involved in apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. Mutations that result in the constitutive activation of this receptor result in acute myeloid leukemia and acute lymphoblastic leukemia. [provided by RefSeq, Jan 2015]. Transcript (Including UTRs) Position: hg19 chr13:28,577,411-28,674,729 Size: 97,319 Total Exon Count: 24 Strand: - Coding Region Position: hg19 chr13:28,578,189-28,674,647 Size: 96,459 Coding Exon Count: 24
ID:FLT3_HUMAN DESCRIPTION: RecName: Full=Receptor-type tyrosine-protein kinase FLT3; EC=2.7.10.1; AltName: Full=FL cytokine receptor; AltName: Full=Fetal liver kinase-2; Short=FLK-2; AltName: Full=Fms-like tyrosine kinase 3; Short=FLT-3; AltName: Full=Stem cell tyrosine kinase 1; Short=STK-1; AltName: CD_antigen=CD135; Flags: Precursor; 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. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. ENZYME REGULATION: Present in an inactive conformation in the absence of bound ligand. FLT3LG binding leads to dimerization and activation by autophosphorylation. SUBUNIT: Monomer in the absence of bound FLT3LG. Homodimer in the presence of bound FLT3LG. Interacts with FIZ1 following ligand activation (By similarity). Interacts with FES, FER, LYN, FGR, HCK, SRC and GRB2. Interacts with PTPRJ/DEP-1 and PTPN11/SHP2. INTERACTION: Q9Y6K9:IKBKG; NbExp=2; IntAct=EBI-3946257, EBI-81279; SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein. Endoplasmic reticulum lumen. 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. TISSUE SPECIFICITY: Detected in bone marrow, in hematopoietic stem cells, in myeloid progenitor cells and in granulocyte/macrophage progenitor cells (at protein level). Detected in bone marrow, liver, thymus, spleen and lymph node, and at low levels in kidney and pancreas. Highly expressed in T-cell leukemia. 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. PTM: N-glycosylated, contains complex N-glycans with sialic acid. PTM: 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. PTM: Rapidly ubiquitinated by UBE2L6 and the E3 ubiquitin-protein ligase SIAH1 after autophosphorylation, leading to its proteasomal degradation. DISEASE: Defects in FLT3 are a cause of acute myelogenous leukemia (AML) [MIM:601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of FLT3 are frequent in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the activation loop of the kinase domain can result in a constitutively activated kinase. MISCELLANEOUS: Can be used as diagnostic tool to establish the exact cause of acute myeloid leukemia, and to determine the optimal therapy. SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. CSF-1/PDGF receptor subfamily. SIMILARITY: Contains 1 Ig-like C2-type (immunoglobulin-like) domain. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/FLT3ID144.html";
leukemia Nanri, T. et al. 2005, Mutations in the receptor tyrosine kinase pathway are associated with clinical outcome in patients with acute myeloblastic leukemia harboring t(8;21)(q22;q22)., Leukemia. 2005 Aug;19(8):1361-6.
[PubMed 15902284]
These results suggest that activating mutations in the RTK pathway play a role in part as an additional event leading to the development of t(8;21) AML. The 6-year cumulative incidence of relapse in patients with RTK pathway mutations was 79.8%, compared with 13.5% in patients lacking such mutations (P=0.0029). Furthermore, the 6-year relapse-free survival in patients with mutations was 18% compared to 60% in those without mutations (P=0.0340), indicating that RTK mutations are associated with the clinical outcome in t(8;21) AML
leukemia, myeloid , D324N single-nucleotide polymorphism in the FLT3 gene is associated with higher risk of myeloid leukemias, Genes, chromosomes & cancer. 2006 Apr;45(4):332-7.
[PubMed 16320249]
Leukemia, Myeloid, Acute Fernando P G Silva , et al. Haematologica 2009 94(11):1546-54, Genome wide molecular analysis of minimally differentiated acute myeloid leukemia., Haematologica 2009 94(11):1546-54.
[PubMed 19773259]
Our results suggest that in patients without RUNX1 mutation, several other molecular aberrations, separately or in combination, contribute to a common minimally differentiated phenotype.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P36888
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
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Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
