Development - Flt3 signaling

Flt3 signaling

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 [1], [2]. 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 [1].

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 [1], [3].

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) [3], [4]. 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) [5], [6], Cas-Br-M ecotropic retroviral transforming sequence (c-Cbl) [5], GRB2-associated binding proteins 1 and 2 (Gab1 and Gab2) [7].

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) [7], [8], [9], v-crk sarcoma virus CT10 oncogene homolog (CRK) and/or v-crk sarcoma virus CT10 oncogene homolog-like (CrkL) [10] participate in transition of FLT3 signaling.

It is known, that FLT3 may activate v-akt murine thymoma viral oncogene homolog (AKT) [9], [11], Mitogen-activated protein kinase ERK [8], [9], [12], Mitogen-activated protein kinase 8 (JNK1) and Mitogen-activated protein kinase p38 [10].

It is proposed, that complex adaptors composed of Shc, c-Cbl, Gab1, Gab2, GRB2, SHP-2, SHIP and CrkL participates in Phosphoinositide-3-kinase (PI3K) activation [7], [8], [9], [10]. Activated PI3K stimulates the conversion of Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) into Phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3). 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) [13].

AKT may suppress apoptosis, for instance, by inhibiting BCL2-antagonist of cell death (BAD) [9], [11].

In addition, it is possible that PI3K may stimulate Guanine nucleotide exchange factor VAV-1, thus participating in JNK and p38 activation, [10], [14].

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) [15]. 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 [16]. FLT3-activated JNK1 have anti-apoptotic function (it is possibly, via inhibition BAD [17]). 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) [18]) and proliferation [10].

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 [16]. p38 phosphorylates Activated transcription factor 2 (ATF-2), in turn, may participate in anti-apoptosis [10].

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) [12] or via other pathways [3], [6], [8]. In addition, FLT3/ ERK pathway participates inhibition BAD by phosphorylation [11], possibly, via Ribosomal protein S6 kinases (p90RSK) [19].

References:

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