Ciliary neurotrophic factor receptors

N.Y. and Yancopoulos, G.D. (1993) Cross-linking identifies leukemia inhibitory factor-binding protein as a ciliary neurotrophic factor receptor component. 7. Biol. Chem. 268 7628-7631. 

Sleeman MW, Anderson KD, Lambert PD et al (2000) The ciliary neurotrophic factor and its receptor, CNTFRa. Pharm Acta Helv 74 265-272... 

FIGURE 27-3 Neurotrophic cytokines and their receptors. Neurotrophic cytokines are related to IL6 and bind to cell surface receptor complexes that share a common structural organization. The four ligands interchangeably employ two distinct receptor subunits, leukemia inhibitory factor receptor 3 (LIF-Rpt) andgpl30, and some employ a ligand-specific a subunit. CNTF-R, ciliary neurotrophic factor CT-fR.cardiotrophin 1 receptor IL6-R, interleukin-6 receptor. 

Cytokine subfamily 2 includes proteins with heterodimeric a—(3 or ct-gpl30 receptors. Thus, granulocyte macrophage colony stimulating factor (GM-GSF), IL-3 and IL-5 act via a—(3 receptors and share (3 receptors. Cardiotrophin-1 (GT-1), ciliary neurotrophic factor (CTNF), IL-6, IL-1, leukaemia inhibitory factor (LIF) and oncostatin M (OSM) act via heterodimeric a-gpl30 receptors with a shared gpl30 receptor subunit. Leucocyte-derived cytokines of this family have immunomodulatory and haematopoietic effects. 

Fig. 3. The gplSO family of cytokines and receptors. Schematic representation of gpl30 and leukemia inhibitory factor receptor (LIFR) oriented in a cell membrane. Of the four-helix bundle gplSO cytokines, structural information currently exists for human interleukin 6 (IL-6) (green) (Somers et al, 1997), human herpes virus interleukin 6 (HlTV-8 IL-6) (purple) (Chow et al, 2001a), ciliary neurotrophic factor (CNTF) (orange) (McDonald et al., 1995), leukemia inhibitory factor (LIF) (blue) (Robinson et al, 1994), and oncostatin-M (OSM) (red) (Deller et al, 2000). Lower panel is a detailed list of gplSO cytokines and the associated receptors incorporated into the final signaling complex. (See Color Insert.)...

Inoue, M., Nakayama, C., Kikuchi, K., Kimura, T., Ishige, Y, Ito, A., Kanaoka, M., and Noguchi, H. (1995). D1 cap region involved in the receptor recognition and neural cell survival activity of human ciliary neurotrophic factor. Proc. Natl. Acad. Sci. USA 92, 8579-8583. 

The neurotrophin family includes NGF, BDNF, neurotrophin-3 (NT-3), NT-4/5, and NT-6. All neurotrophins are capable of binding to the p75 receptor each neurotrophin also binds to a specific Trk receptor. Trk is the receptor for NGF TrkB is the receptor for BDNF and NT-4, while TrkC is the receptor for NT-3. Neurotrophins secreted by cells protect neurons from apoptosis (Korsching, 1993 Lewin and Barde, 1996). Similarly, ciliary neurotrophic factor (CNTF), a structurally related type I cytokine and GDNF, structurally related to TGF-[3, each constitute a sub-family of neurotrophic factors. 

The increased number of new ly generated cells in the SGZ follow ing hfe-style modulators, is thought to be due to the increase in cell survival and has been linked to increased protein levels for both BDNF and neurotrophin 3 (NT-3) (Lee et al., 2000, 2002 Duan et al., 2001). Ciliary neurotrophic factor (CNTF) is an acidic protein involved in type-2 astrocyte differentiation. Injection of CNTF into the mouse brain stimulates precursor cell proliferation w ith the CNTF receptor alpha expressed on GFAP-positive cells of the SVZ (Fmsley and Hagg, 2003). 

Lee DA, Gross L, Wittrock DA, Windebank AJ (1997) Differential regulation of ciliary neurotrophic factor (CNTF) and CNTF receptor alpha expression in astrocytes and neurons of the facia dentata after entorhinal cortex lesion. J Neurosci 17 1137-1146. 

Hagg, T., Varon, S., and Louis, J. C., Ciliary neurotrophic factor (CNTF) promotes low-affinity nerve growth factor receptor and CD4 expression by rat CNS microglia, J. Neuroimmunol., 48, 177, 1993. 

Hagg, T., Quon, D., Higaki, J., and Varon, S., Ciliary neurotrophic factor prevents neuronal degeneration and promotes low affinity NGF receptor expression in the adult rat CNS, Neuron, 8, 145, 1992. 

Keywords Nerve growth factor (NGF) Brain-derived neurotrophic factor (BDNF) Glial cell line-derived neurotrophic factor (GNTF) Ciliary neurotrophic factor (CNTF) Insulin-like growth factor-I (IGF-1) Death receptors... 

Di Marco, A., Gloaguen, I., Graziani, R., Paonessa, G., Saggio, I., Hudson, K.R., Laufer, R., 1996. Identification of ciliary neurotrophic factor (CNTF) residues essential for leukemia inhibitory factor receptor binding and generation of CNTF receptor antagonists. Proc. Natl. Acad. Sci. U.S.A. 93, 9247-9252. 

Trophic factors exemplified by NGF and its family members, ciliary neurotrophic factor (CNTF) and glial derived neurotrophic factor (GDNF) all utilize increased tyrosine phosphorylation of cellular substrates to mediate neuronal cell survival. Actions of the NGF family of neurotrophins are not only dictated by ras activation through the Trk family of receptor tyrosine kinases, but also a survival pathway defined by phosphatidylinositol-3-kinase activity (Yao and Cooper, 1995), which gives rise to phosphoinositide intermediates that activate the serine/ threonine kinase Akt/PKB (Dudek et al., 1997). Induction of the serine-threonine kinase activity is critical for cell survival, as well as cell proliferation. Hence, for many trophic factors, multiple proteins constitute a functional multisubunit receptor complex that activates rai-depen-dent and ras-independent intracellular signaling. 

DiStefano, P.S., Boulton, T.G., Stark, J.L., Zhu, Y Adryan, K.M., Ryan, T.E., Lindsay, R.M., 1996. Ciliary neurotrophic factor induces down-regulation of its receptor and desensitization of signal transduction pathways in vivo non-equivalence with pharmacological activity. J. Biol. Chem. 271 (37), 22839-22846. 

Kallen, K.J., Grotzinger, J., Lelievre, E., Vollmer, P., Aasland, D., Renne, C., Mullberg, J., Myer zum Buschenfelde, K.H., Gascan, H., Rose-John, S., 1999. Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6. J. Biol. Chem. 274 (17). 11859-11867. 

Nesbitt, J.E., Fuentes, N.L., Fuller, G.M., 1993. Ciliary neurotrophic factor regulates fibrinogen gene expression in hepatocytes by binding to the interleukin-6 receptor. Biochem. Biophys. Res. Common. 190, 544-550. 

Panayotatos, N., Radziejewska, E., Acheson, A., Somogyi, R., Thadani, A., Hendrickson, W.A., McDonald, N.Q., 1995. Localization of functional receptor epitopes on the structure of ciliary neurotrophic factor indicates a conserved, function-related epitope topography among helical cytokines. J. Biol. Chem. 270 (23), 14007-14014. 

A number of proteins influence neurotransmitter traits in sympathetic neurons (Fukada, 1985 Kessler et al., 1986 Saadat et al., 1989). Sympathetic cholinergic differentiating factor and leukemia inhibitory factor are the same 45 kDa glycoprotein molecule (Yamamori et al., 1989) which increases CAT activity and decreases tyrosine hydroxylase activity (Fukada, 1985). A 22 kDa protein isolated from rat sciatic nerve, ciliary neurotrophic factor (Manthorpe et al., 1986 Lin et al., 1989 Stockii et al., 1989) has a similar effect (Saadat et al., 1989). It appears that the two molecules act via the same receptor complex (Ip et al.,... 

Nucleotide sequences does not immediately reveal the level of homology of various factors to LIF. However, similarity of effects of IL-6 and LIF on myeloid leukemia cell lines suggest that they may share the same receptors and the same signal transduction pathways (Gough and Williams, 1989 Gough et al., 1989). The similar activities of CNTF (ciliary neurotrophic factor) and CDF/LIF in induction of neurotransmitter changes in sympathetic neurons supports this hypothesis (Saadat et al., 1989 Yamamori et al.,1989 Ya-mamori, 1992). 

Gearing, D.P., Ziegler, S.F., Comeau, M.R., Friend, D., Thoma, B., Cosman, D., Park, L. and Mosley B. (1994) Proliferative responses and binding properties of hematopoietic cells transfected with low-affinity receptors for leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor. Proc. Natl. Acad. Sci. USA 91 1119-1123. 

Ludlam, W.H. and Kessler, J.A. (1993) Leukemia inhibitory factor and ciliary neurotrophic factor regulate expression of muscarinic receptors in cultured sympathetic neurons. Dev. Biol. 155 497-506. 

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