Class III FLT3 (Fms-like Tyrosine Kinase-3)
RTKs - Receptor Tyrosine Kinases

Author: giulia aghemo
Date: 26/10/2009

Description

DEFINITION

Other name: FLK2 (Fetal Liver Kinase-2); hSTK1 (human Stem Cell Kinase-1)
Type of protein: class III receptor tyrosine kinase (RTK)
Molecolar weight: 160 kDa
Ligand: (FL/Flt-3L) :a type I transmembrane glycoprotein of approximately 30 kDa.
FLT3 gene:
LOCATION:13q12.2
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.
TRASCRIPTION: 3.7 kb; 2979 bp open reading frame

CHEMICAL STRUCTURE

Ribbon and surface diagrams of FLT3 showing the spatial arrangement of the various structural elements of the molecule. The N-terminal kinase domain (red) and the C-terminal kinase domain (blue) comprise the standard kinase fold. The activation loop (green) is folded up between the two kinase domains. The JM domain (yellow) nearly spans the length of molecule. All tyrosines in the JM domain and the activation loop are displayed as "stick" representations. (B) Same as (A), except the molecule is rotated 90_ clockwise when viewed down the vertical axis.

PROTEIN AMINOACID PERCENTAGE

FLT3 SYNTHESIS AND TURNOVER

Transcription of the FLT3 gene produces FLT3 mRNA, which is translated to FLT3 protein. FLT3 contains five extracellular immunoglobulin-like domains (E), a transmembrane domain (T M), a juxtamembrane domain (JM) and two tyrosine-kinase domains (K) that are linked through the tyrosine-kinase insert (KI). Cytoplasmic FLT3 undergoes glycosylation (G), which promotes localization of the receptor to the membrane. Wild-type FLT3 remains as a monomeric, inactivated protein on the cell surface until FLT3 ligand (L), probably in a dimeric form, binds the receptor and induces receptor dimerization. FLT3 dimerization promotes phosphorylation (P) of the tyrosine-kinase domains, thereby activating the receptor and downstream effectors. The dimerized receptors are quickly internalized and degraded.

THE FLT3 EXPRESSION IN NORMAL HAEMATOPOIESIS

The maturation and differentiation of cells during normal haematopoiesis and the expression of FLT3 linked to this process (shown as +, - , +/ - or ? (unknown)). FLT3 is mainly expressed by early myeloid and lymphoid progenitor cells, with some expression by the more mature monocytic lineage cells.

THE FLT3 SIGNALING CASCATE

Although the FLT3 signalling cascade has not been definitively characterized, there are some of the complex associations and downstream effects that probably occur after activation of FLT3. Binding of FLT3L to FLT3 triggers the PI3K and RAS pathways, leading to increased cell proliferation and the inhibition of apoptosis. PI3K activity is probably regulated through various interactions between FLT3, SH2-containing sequence proteins (SHCs) and one or more other proteins, such as SH2-domain-containing inositol phosphatase (SHIP), SH2-domain containing protein tyrosine phosphatase 2 (SHP2), CBL (a proto-oncogene) and GRB2-binding protein (GAB2). Activated PI3K stimulates downstream proteins such as 3-phosphoinositide-dependent protein kinase 1 (PDK1), protein kinase B (PKB/AKT) and the mammalian target of rapamycin (mTOR), which initiate the transcription and translation of crucial regulatory genes through the activation of p70 S6 kinase (S6K) and the inhibition of eukaryotic initiation factor 4E-binding protein (4E-BP1). In addition, PI3K activation blocks apoptosis through phosphorylation of the pro-apoptotic BCL2-family protein BAD (BCL2 antagonist of cell death). Activated FLT3 also associates with GRB2 through SHC, so activating RAS. RAS activation stimulates downstream effectors such as RAF, MAPK/ERK kinases (MEKs), extracellular-signal-regulated kinase (ERK), and the 90-kDa ribosomal protein S6 kinase (RSK). These downstream effectors activate cyclic adenosine monophosphate-response element binding protein (CREB), ELK and signal transducer and activators of transcription (STATs), which lead to the transcription of genes involved in proliferation. Both pathways probably also interact with many other antiapoptotic and cell-cycle proteins, such as WAF1, KIP1 and BRCA1.

FLT3 AND DISEASE

The FLT3 internal tandem duplication (ITD) results from a head-to-tail duplication of 3 - 400 base pairs in exons 14 or 15,which encode the juxtamembrane domain of FLT3.
Point mutations in FLT3 occur in heavily conserved areas of the intracellular tyrosinekinase domain (TKD),homologous to point mutations that are seen in other RTKs such as KIT and FMS.

FLT3mutations are the most frequent genetic lesion seen in acute myeloid leukaemia (AML). The prevalence of FLT3 ITDs is 15 - 35%,with an additional 5 - 10% of patients
having FLT3 TKD mutations. Both types of FLT3 mutation cause ligand-independent activation of the receptor and activation of downstream signalling pathways. The presence of a FLT3 ITD is associated with poor clinical outcome in both paediatric and adult patients with AML.
Internal tandem duplications and/or insertions 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.

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