FMS-like tyrosine kinase 3 (FLT3) belongs to the
subclass III family of receptor tyrosine kinases and it is expressed mainly in early
myeloid and lymphoid progenitor cells. Its activation leads mainly to proliferation and
survival , . FLT3 consists
of five immunoglobulin-like extracellular domains, a transmembrane domain, a
juxtamembrane domain and two intracellular tyrosine kinase domains linked by a
kinase-insert domain .
FLT3 ligand binds the monomeric form of
FLT3 receptor and induces receptor dimerization. This
promotes autophosphorylation of the tyrosine-kinase domains
FLT3, thereby activating the
FLT3 and downstream effectors , .
The exact mechanism of action FLT3 remains unknown. It
was is proposed that activated FLT3 stimulates some members
of Src family of protein tyrosine kinases (e.g., c-src sarcoma viral oncogene homolog
(c-Src) or Fyn) , . Then these tyrosine kinases (or some other tyrosine kinases)
may phosphorylate several adaptor proteins. For example, there are Src homology 2 domain
containing transforming protein 1 (Shc) , , Cas-Br-M ecotropic retroviral transforming sequence
(c-Cbl) , GRB2-associated binding proteins 1
and 2 (Gab1 and Gab2) .
These proteins along with Growth factor receptor-bound protein
(GRB2), Protein tyrosine phosphatase, non-receptor type 11
(SHP-2), Inositol polyphosphate-5-phosphatase, 145kDa
(SHIP) , , ,
v-crk sarcoma virus CT10 oncogene homolog (CRK) and/or v-crk
sarcoma virus CT10 oncogene homolog-like (CrkL)  participate in transition of FLT3 signaling.
It is known, that FLT3 may activate
v-akt murine thymoma viral oncogene homolog
(AKT) , , Mitogen-activated
protein kinase ERK , , , Mitogen-activated protein kinase 8 (JNK1)
and Mitogen-activated protein kinase p38 .
It is proposed, that complex adaptors composed of Shc,
SHP-2, SHIP and
CrkL participates in
Phosphoinositide-3-kinase (PI3K) activation
, , , . Activated
PI3K stimulates the conversion of
Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) into
PI(3,4,5)P3 binds to the pleckstrin-homology domain of
AKT, recruits AKT to the plasma
membrane, and exposes AKT to Phosphorylation at by
3-phosphoinositide-dependent protein kinase 1 (PDK) .
AKT may suppress apoptosis, for instance, by inhibiting
BCL2-antagonist of cell death (BAD) , .
In addition, it is possible that PI3K may stimulate
Guanine nucleotide exchange factor VAV-1, thus participating
in JNK and p38 activation,
It is known, that VAV-1 may activate members RAS
superfamily of small GTP-binding proteins, e.g. Ras-related C3 botulinum toxin substrate
1 (Rac1) and Cell division cycle 42
(CDC42) . Then, activated
Rac1 and CDC42 may stimulate
p21-activated kinase 1 (PAK1)/ Mitogen-activated protein
kinase kinase kinase 1 (MEKK1)/ Dual specificity
mitogen-activated protein kinase kinase 4 (MEK4) and/or 7
(MEK7)/ JNK1 cascade . FLT3-activated JNK1
have anti-apoptotic function (it is possibly, via inhibition BAD
). In addition, JNK1
phosphorylates transcription factor Jun oncogene
(c-Jun), which participates in anti-apoptosis (probably,,
via activation of transcription BCL2-like 1 (Bcl-XL) ) and proliferation .
Moreover, Rac1 and CDC42 may
stimulate Mitogen-activated protein kinase kinase kinase 4
(MEKK4)/ Dual specificity mitogen-activated protein kinase
kinase 3 (MEK3) and/or 6 (MEK6)/ p38 cascade .
p38 phosphorylates Activated transcription factor 2
(ATF-2), in turn, may participate in anti-apoptosis .
On the other hand, FLT3-activated
adaptors Shc and
GRB2 participate in ERK
activation via Son of sevenless (SOS)/ Harvey rat sarcoma
virus oncogene (H-Ras)/ v-raf-1 murine leukemia viral
oncogene homolog 1 (c-Raf-1)/ MAPK kinase 1
(MEK1) and 2 (MEK2)/
Erk cascade. Erk cascade
stimulates proliferation of hematopoietic cells, e.g. via phosphorylation Signal
transducer and activator of transcription 5A (STAT5A)  or via other pathways , , . In
addition, FLT3/ ERK pathway
participates inhibition BAD by phosphorylation , possibly, via Ribosomal protein S6 kinases
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