FLT3
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]
Full Name
Fms Related Tyrosine Kinase 3
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.
Biological Process
Animal organ regeneration Source: Ensembl
B cell differentiation Source: UniProtKB
Cellular response to cytokine stimulus Source: UniProtKB
Cellular response to glucocorticoid stimulus Source: Ensembl
Common myeloid progenitor cell proliferation Source: UniProtKB
Cytokine-mediated signaling pathway Source: UniProtKB
Dendritic cell differentiation Source: UniProtKB
Hemopoiesis Source: MGI
Leukocyte homeostasis Source: UniProtKB
Lymphocyte proliferation Source: UniProtKB
Myeloid progenitor cell differentiation Source: UniProtKB
Peptidyl-tyrosine phosphorylation Source: UniProtKB
Positive regulation of cell population proliferation Source: UniProtKB
Positive regulation of kinase activity Source: GO_Central
Positive regulation of MAPK cascade Source: UniProtKB
Positive regulation of MAP kinase activity Source: UniProtKB
Positive regulation of phosphatidylinositol 3-kinase activity Source: UniProtKB
Positive regulation of phosphatidylinositol 3-kinase signaling Source: UniProtKB
Positive regulation of tyrosine phosphorylation of STAT protein Source: UniProtKB
Pro-B cell differentiation Source: UniProtKB
Protein autophosphorylation Source: UniProtKB
Regulation of apoptotic process Source: UniProtKB
Response to organonitrogen compound Source: Ensembl
Transmembrane receptor protein tyrosine kinase signaling pathway Source: GO_Central
Cellular Location
Endoplasmic reticulum lumen; Membrane. 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.
Involvement in disease
Leukemia, acute myelogenous (AML):
The gene represented in this entry may be involved in disease pathogenesis. 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.
A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes.
Topology
Extracellular: 27-543
Helical: 544-563
Cytoplasmic: 564-993
PTM
N-glycosylated, contains complex N-glycans with sialic acid.
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.
Rapidly ubiquitinated by UBE2L6 and the E3 ubiquitin-protein ligase SIAH1 after autophosphorylation, leading to its proteasomal degradation.
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