FLT3_HUMAN » Receptor-type tyrosine-protein kinase FLT3

FLT3_HUMAN » Receptor-type tyrosine-protein kinase FLT3
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Topology in Plasma membrane
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FLT3_HUMAN » Receptor-type tyrosine-protein kinase FLT3 » FL cytokine receptor;Fetal liver kinase-2;FLK-2; Fms-like tyrosine kinase 3;FLT-3; Stem cell tyrosine kinase 1;STK-1;
Hydrophobic Thickness 32.4 ± 0.6 Å
Tilt Angle 4 ± 2°
ΔGtransfer -44.3 kcal/mol
ΔGfold -20.4 kcal/mol
Links UniProtKB, Pfam, Interpro, iHOP, STRING, HGNC, HMDB
Topology Out
TM Segments 543-566 (542-568)
Pathways

Acute myeloid leukemia (KEGG)

Cytokine-cytokine receptor interaction (KEGG)

Hematopoietic cell lineage (KEGG)

Pathways in cancer (KEGG)

Transcriptional misregulation in cancer (KEGG)

PDB 1rjb (564-907), 3qs7 (E/F/G/H=27-436), 3qs9 (E/F/G/H=27-540)
OPM none
Complexes

FLT3:FLT3L_HUMAN

Interactions

FLT3L, Complex: FLT3L:FLT3, PubMed

PTPRJ, Complex: FLT3:PTPRJ

Domains

AA: 255-345, PDBID: 3QS7, Subunit G, Seq Identity:100%, Immunoglobulin domain

AA: 610-943, PDBID: 1RJB, Subunit A, Seq Identity:100%, Protein tyrosine kinase

UniProt annotation for FLT3_HUMAN » Receptor-type tyrosine-protein kinase FLT3
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. Interacts with RNF115 and RNF126 (By similarity).

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.

DISEASE: Leukemia, acute myelogenous (AML) OMIM: 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. 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.

MISCELLANEOUS: Can be used as diagnostic tool to establish the exact cause of acute myeloid leukemia, and to determine the optimal therapy.

UniProt features for FLT3_HUMAN » Receptor-type tyrosine-protein kinase FLT3
SIGNAL 1 26 Potential.
CHAIN 27 993 Receptor-type tyrosine-protein kinase FLT3.
DOMAIN 253 343 Ig-like C2-type.
DOMAIN 610 943 Protein kinase.
REGION 591 597 Important for normal regulation of the kinase activity and for maintaining the kinase in an inactive state in the absence of bound ligand.
ACT_SITE 811 811 Proton acceptor (By similarity).
DISULFID 35 65
DISULFID 103 114
DISULFID 199 206
DISULFID 232 241
DISULFID 272 330
DISULFID 368 407
DISULFID 381 392
Amino Acid Sequence for FLT3_HUMAN » Receptor-type tyrosine-protein kinase FLT3
MPALARDGGQ LPLLVVFSAM IFGTITNQDL PVIKCVLINH KNNDSSVGKS SSYPMVSESP EDLGCALRPQ SSGTVYEAAA VEVDVSASIT LQVLVDAPGN ISCLWVFKHS SLNCQPHFDL QNRGVVSMVI LKMTETQAGE YLLFIQSEAT NYTILFTVSI RNTLLYTLRR PYFRKMENQD ALVCISESVP EPIVEWVLCD SQGESCKEES PAVVKKEEKV LHELFGTDIR CCARNELGRE CTRLFTIDLN QTPQTTLPQL FLKVGEPLWI RCKAVHVNHG FGLTWELENK ALEEGNYFEM STYSTNRTMI RILFAFVSSV ARNDTGYYTC SSSKHPSQSA LVTIVEKGFI NATNSSEDYE IDQYEEFCFS VRFKAYPQIR CTWTFSRKSF PCEQKGLDNG YSISKFCNHK HQPGEYIFHA ENDDAQFTKM FTLNIRRKPQ VLAEASASQA SCFSDGYPLP SWTWKKCSDK SPNCTEEITE GVWNRKANRK VFGQWVSSST LNMSEAIKGF LVKCCAYNSL GTSCETILLN SPGPFPFIQD NISFYATIGV CLLFIVVLTL LICHKYKKQF RYESQLQMVQ VTGSSDNEYF YVDFREYEYD LKWEFPRENL EFGKVLGSGA FGKVMNATAY GISKTGVSIQ VAVKMLKEKA DSSEREALMS ELKMMTQLGS HENIVNLLGA CTLSGPIYLI FEYCCYGDLL NYLRSKREKF HRTWTEIFKE HNFSFYPTFQ SHPNSSMPGS REVQIHPDSD QISGLHGNSF HSEDEIEYEN QKRLEEEEDL NVLTFEDLLC FAYQVAKGME FLEFKSCVHR DLAARNVLVT HGKVVKICDF GLARDIMSDS NYVVRGNARL PVKWMAPESL FEGIYTIKSD VWSYGILLWE IFSLGVNPYP GIPVDANFYK LIQNGFKMDQ PFYATEEIYI IMQSCWAFDS RKRPSFPNLT SFLGCQLADA EEAMYQNVDG RVSECPHTYQ NRRPFSREMD LGLLSPQAQV EDS