Pathway Map Details

Development_CNTF receptor signaling

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CNTF receptor, c-Raf-1, PI3K reg class IA, p70 S6 kinase2, Tuberin, MEK2(MAP2K2), SOS, RHEB2, SOCS3, CLF-1, glycosylphosphatidylinositol, CNTFR alpha, gp130, ATP + phosphatidylinositol 4,5-bisphosphate = ADP + phosphatidylinositol 3,4,5-trisphosphate, Shc, JAK2, H-Ras, ERK1/2, JAK1, PtdIns(4,5)P2, SHP-2, PI3K cat class IA, c-Fos, STAT3, BSF-3 (cardiotrophin-like cytokine), p70 S6 kinase1, CNTF, PtdIns(3,4,5)P3, GRB2, STAT1, LIFR, AKT(PKB), mTOR, MEK1(MAP2K1)


CNTF receptor signaling

Ciliary neurotrophic factor receptor ( CNTF receptor) is a tripartite complex formed by a specific alpha subunit Ciliary neurotrophic factor receptor ( CNTFR alpha ) and two beta subunits, Leukemia inhibitory factor receptor ( LIFR ) and Interleukin 6 signal transducer ( gp130 ). CNTF receptor is implicated in multiple signal transduction pathways [1], [2], [3]. CNTFR alpha is active in either membrane-bound, or soluble form. [4]. Membrane-bound CNTFR alpha is anchored to the plasma membrane by a glycosylphosphatidylinositol linkage [5], [6].

Signal transduction pathways activated by stimulation of CNTF receptor affect survival, regeneration, proliferation, differentiation, activation or cell death in different cell types [3], [6], [7].

Two ligands of CNTF receptor are Ciliary neurotrophic factor ( CNTF ) and Cardiotrophin-like cytokine ( BSF-3 (cardiotrophin-like cytokine) ) that associates with the soluble orphan receptor cytokine-like factor-1 ( CLF-1 ) to form a functional heteromeric ligand for the CNTF receptor complex. heterodimeric composite cytokine [8], [9], [10]

The main difference between BSF-3 (cardiotrophin-like cytokine)/ CLF-1 and CNTF is that the former only binds to the membrane bound form of CNTFR alpha, while CNTF binds both soluble, and membrane bound forms [6].

Intracellular signaling through CNTF receptor involves three major signal transduction pathways: Janus kinases (JAKs)/ Signal transducer and activators (STATs) [9], [11], [12], Mitogen-activated protein kinases 1-3 ( ERK1/2 ) [9], [11], [12], and Phosphatidylinositol 3-kinase ( PI3K )/ V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB) ) signaling cascades [13], [9], [14].

Formation of CNTF receptor complex leads to activation of JAKs / STATs pathways [15], [8], [12]. STATs then translocate to the nucleus where they activate transcription of target genes such as cellular oncogene v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) [11], [16], Suppressor of cytokine signaling 3 ( SOCS-3 ) [16] or certain gap junctional proteins [12].

SOCS-3 can inhibit CNTF signaling [17], probably via inhibition of JAKs and/or gp130 subunit [18].

In addition, JAK2 phosphorylates CNTF receptor -activated Protein tyrosine phosphatase, non-receptor type 11 ( SHP-2 ) [19], [20], [9]. SHP-2 inhibits JAKs / STATs pathway via dephosphorylation of JAK2 and/or LIFR/ gp130 heterodimer [20], [18]. On the other hand, CNTF receptor -activated SHP-2 induces activation of ERK1/2 and PI3K signaling cascades [9]

JAK2 and JAK2 -activated SHP-2 activates PI3K/ AKT(PKB). AKT(PKB) and stimulates cell survival [6], [7], as well as accelerates necrotic cell death during hypoxia [21], [7]. In addition, PI3K/ AKT(PKB) activates FK506 binding protein 12-rapamycin associated protein 1 ( mTOR )/ ribosomal protein S6 kinase, 70kDa, polypeptides 1 and 2 ( p70 S6 kinase 1, p70 S6 kinases 2 ) signaling cascades, thus stimulating translation [9], [14]. CNTF -activated mTOR may phosphorylate Signal transducer and activator of transcription 3 ( STAT3 ) and thus regulates transcription of STAT3 target genes [13].

Moreover, JAK2 and JAK2 -activated SHP-2 activates Src homology 2 domain containing transforming protein 1 ( Shc )/ Growth factor receptor-bound protein 2 ( Grb2 )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( 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 [9], [11], [14]. It is possible, that activation of the c-Fos is one of the functions of the CNTF receptor -activated ERK1/2 [11], [22], [16].


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