Development Flt3 signaling
Flt3 signaling FMS-like tyrosine kinase 3 ( FLT3 ) belongs to the subclass III family ofreceptor tyrosine kinases and it is expressed mainly in early myeloid and lymphoidprogenitor cells. Its activation leads mainly to proliferation and survival , . FLT3 consists of five immunoglobulin-likeextracellular domains, a transmembrane domain, a juxtamembrane domain and twointracellular tyrosine kinase domains linked by a kinase-insert domain . FLT3 ligand binds the monomeric form of FLT3 receptor and inducesreceptor dimerization. This promotes autophosphorylation of the tyrosine-kinase domainsFLT3, thereby activating the FLT3 and downstream effectors , . The exact mechanism of action FLT3 remains unknown. It was is proposed thatactivated 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 domaincontaining 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 ), Inositolpolyphosphate-5-phosphatase, 145kDa ( SHIP ) , ,, v-crk sarcoma virus CT10 oncogene homolog ( CRK ) and/or v-crksarcoma virus CT10 oncogene homolog-like ( CrkL )  participate intransition of FLT3 signaling. It is known, that FLT3 may activate v-akt murine thymoma viral oncogene homolog( AKT ) , , Mitogen-activated protein kinaseERK , , , Mitogen-activatedprotein kinase 8 ( JNK1 ) and Mitogen-activated protein kinase p38 . It is proposed, that complex adaptors composed of Shc, c-Cbl,Gab1, Gab2, GRB2, SHP-2, SHIP and CrkLparticipates in Phosphoinositide-3-kinase ( PI3K ) activation ,, , . Activated PI3K stimulatesthe conversion of Phosphatidylinositol-4,5-bisphosphate ( PI(4,5)P2 ) intoPhosphatidylinositol-3,4,5-trisphosphate ( PI(3,4,5)P3 ). PI(3,4,5)P3 bindsto the pleckstrin-homology domain of AKT, recruits AKT to the plasmamembrane, and exposes AKT to Phosphorylation at by 3-phosphoinositide-dependentprotein kinase 1 ( PDK ) . AKT may suppress apoptosis, for instance, by inhibiting BCL2-antagonist of celldeath ( BAD ) , . In addition, it is possible that PI3K may stimulate Guanine nucleotide exchangefactor VAV-1, thus participating in JNK and p38 activation, , . It is known, that VAV-1 may activate members RAS superfamily of smallGTP-binding proteins, e.g. Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) andCell division cycle 42 ( CDC42 ) . Then, activated Rac1and CDC42 may stimulate p21-activated kinase 1 ( PAK1 )/ Mitogen-activatedprotein kinase kinase kinase 1 ( MEKK1 )/ Dual specificity mitogen-activatedprotein kinase kinase 4 ( MEK4 ) and/or 7 ( MEK7 )/ JNK1 cascade. FLT3 -activated JNK1 have anti-apoptotic function (it ispossibly, via inhibition BAD ). In addition, JNK1phosphorylates transcription factor Jun oncogene ( c-Jun ), which participates inanti-apoptosis (probably,, via activation of transcription BCL2-like 1 ( Bcl-XL )) and proliferation . Moreover, Rac1 and CDC42 may stimulate Mitogen-activated protein kinasekinase kinase 4 ( MEKK4 )/ Dual specificity mitogen-activated protein kinasekinase 3 ( MEK3 ) and/or 6 ( MEK6 )/ p38 cascade .p38 phosphorylates Activated transcription factor 2 ( ATF-2 ), in turn, mayparticipate in anti-apoptosis . On the other hand, FLT3 -activated adaptors Shc and GRB2participate in ERK activation via Son of sevenless ( SOS )/ Harvey ratsarcoma virus oncogene ( H-Ras )/ v-raf-1 murine leukemia viral oncogene homolog1 ( c-Raf-1 )/ MAPK kinase 1 ( MEK1 ) and 2 ( MEK2 )/ Erkcascade. Erk cascade stimulates proliferation of hematopoietic cells, e.g. viaphosphorylation Signal transducer and activator of transcription 5A ( STAT5A ), , . In addition, FLT3/ ERK pathway participates inhibitionBAD by phosphorylation , possibly, via Ribosomal protein S6kinases ( p90RSK ) .