Development CNTF receptor signaling
CNTF receptor signaling Ciliary neurotrophic factor receptor ( CNTF receptor) is a tripartite complexformed by a specific alpha subunit Ciliary neurotrophic factor receptor ( CNTFRalpha ) , and two beta subunits - Leukemia inhibitory factor receptor (LIFR ) and Interleukin 6 signal transducer ( gp130 ), coupled to multiplesignal transduction pathways , , . CNTFRalpha is active in either membrane-bound or soluble form. .Membrane-bound CNTFR alpha is anchored to the plasma membrane by aglycosylphosphatidylinositol linkage , . Signal transduction pathways, activated by stimulation of CNTF receptor affectsurvival, regeneration, proliferation, differentiation, activation or cell death indifferent cell types , , . Two ligands of CNTF receptor are Ciliary neurotrophic factor ( CNTF )and heterodimeric composite cytokine which consist from Cardiotrophin-like cytokine (BSF-3 (cardiotrophin-like cytokine) ). Both ligands are associated with thesoluble orphan receptor cytokine-like factor-1 ( CLF-1 ) , ,  The main difference between BSF-3 (cardiotrophin-like cytokine)/ CLF-1and CNTF is that the former only binds to the membrane bound form of CNTFRalpha, while CNTF binds both the soluble and the membrane bound forms . Intracellular signaling through CNTF receptor involves three major signaltransduction pathways: Janus kinases (JAKs)/ Signal transducer and activators (STATs), , , Mitogen-activated protein kinases1-3 ( ERK1/2 ) , ,  andPhosphatidylinositol 3-kinase ( PI3K )/ V-akt murine thymoma viral oncogenehomolog 1 ( AKT(PKB) ) signaling cascades, ,. Formation of CNTF receptor complex leads to activation of JAKs / STATspathways , , .Then STATs translocate tothe nucleus where they activate transcription of target genes such as cellular oncogenev-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) ,, Suppressor of cytokine signaling 3 ( SOCS-3 ) or certain gap junctional proteins . SOCS-3 can inhibit CNTF signaling , probably viainhibition of JAKs and/or gp130 subunit . In addition, JAKs may participate in phosphorylation of CNTF receptor-activated Protein tyrosine phosphatase, non-receptor type 11 ( SHP-2 ) , , . SHP-2 as shown to inhibit JAKs/ STATs pathway via JAKs and/or LIFR/ gp130 heterodimer , . On the other hand, CNTF receptor -activatedSHP-2 promotes activation of ERK1/2 and PI3K signaling cascades JAK2 and JAK2 -activated SHP-2 may activate PI3K/AKT(PKB). AKT(PKB) may stimulate cell survival , and accelerate necrotic cell death during hypoxia , . Inaddition, PI3K/ AKT(PKB) activates FK506 binding protein 12-rapamycinassociated protein 1 ( mTOR )/ ribosomal protein S6 kinase, 70kDa, polypeptides 1and 2 ( p70 S6 kinase 1, p70 S6 kinases 2 ) signaling cascades, thus stimulatingtranslation , . CNTF -activated mTOR mayphosphorylate Signal transducer and activator of transcription 3 ( STAT3 ),regulating transcription of STAT3 -target genes . Moreover, JAK2 and JAK2 -activated SHP-2 may activate Srchomology 2 domain containing transforming protein 1 ( Shc )/ Growth factorreceptor-bound protein 2 ( Grb2 )/ v-Ha-ras Harvey rat sarcoma viral oncogenehomolog ( H-Ras )/ v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1 )/ Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1)and MEK2(MAP2K2) )/ ERK1/2 cascade , ,. It is possible, that activation c-Fos is one of functions ofCNTF receptor -activated ERK1/2 , , .