Pathway Map Details

Development_Flt3 signaling

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Object list (links open in MetaCore):

Fyn, PDK (PDPK1), GAB2, PI3K reg class IA (p85), CRK, MEKK1(MAP3K1), GAB1, p38 MAPK, SHP-2, MEK3(MAP2K3), MEK4(MAP2K4), c-Cbl, GRB2, c-Src, CDC42, CrkL, PAK1, PI3K cat class IA, SOS, FLT3, H-Ras, MKK7 (MAP2K7), p90Rsk, PtdIns(4,5)P2, AKT(PKB), PtdIns(3,4,5)P3, MEK2(MAP2K2), MEK6(MAP2K6), MEKK4(MAP3K4), VAV-1, Bcl-XL, JNK1(MAPK8), BAD, STAT5A, MEK1(MAP2K1), ATF-2,, SHIP, c-Raf-1, FLT3 ligand, Erk (MAPK1/3), Rac1, c-Jun, Shc


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 ) [4], [3]. 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 ) [8], [7], [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 ) [11], [9], Mitogen-activated protein kinase ERK [8], [12], [9], 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 [8], [7], [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 ) [11], [9].

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

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


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