Development - CNTF receptor signaling

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) {PMID: 11294841}, [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[9], [13], [14].

Formation of CNTF receptor complex leads to activation of JAKs/ STATs pathways [8], [12], [15]. 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], {PMID: 11294841}. SHP-2 inhibits JAKs/ STATs pathway via dephosphorylation of JAK2 and/or LIFR/gp130 heterodimer [18], [20]. 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 [7], [21]. 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 {PMID: 11294841}, [11], [14]. It is possible, that activation of the c-Fos is one of the functions of the CNTF receptor-activated ERK1/2 [11], [16], [22].

References:

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