CLF:CLC Complex: A Second Ligand for the CNTF Receptor

CLF-1 (Cytokine-Like Factor-1), also identified as NR6, is a secreted protein that shares considerable sequence and structural similarities with members of the cytokine type I receptor family.^1-4 CLF-1 associates with cardiotrophin-like cytokine (CLC),⁵ also called NNT-1/BSF-3,⁶ to form the second identified ligand for the ciliary neurotrophic factor receptor complex (CNTF R). Similar to CNTF, heterodimeric CLF-1/CLC binds to CNTF R alpha, thereby activating signaling through gp130 and LIF R beta, the signaling subunits of the tripartite CNTF R complex. CLF-1/CLC can sustain the in vitro survival of embryonic neurons, implicating CLF-1/CLC with a potentially important role in nervous system development.⁴

The observation that CNTF null mice appear largely normal, while the disruption of the CNTF R alpha gene results in perinatal death, suggests the existence of a second important ligand for CNTF R. The phenotypic similarity between mice deficient for the CLF-1 gene and mice null for CNTF R alpha, identifies CLF-1 as a likely candidate for the second ligand.² Furthermore, the structural homology between CLF-1 and the p40 subunit of IL-12 suggests that CLF-1 may be part of a heteromeric ligand complex similar to IL-12, which is composed of two covalently linked polypeptide chains, designated IL-12 p35 and IL-12 p40. The second component of the hypothesized heterodimeric ligand, identified as CLC (Cardiotrophin-like Cytokine), not only shares homology with CNTF, but also resembles IL-12 p35. Both IL-12 p35 and CLC display homology with IL-6 type cytokines and are poorly secreted. In contrast to IL-12 p35, which lacks demonstrable bioactivity in the absence of IL-12 p40, CLC can by itself potentiate biological effects similar to those mediated by the CLF-1/CLC heterodimer. E. coli-produced CLC induces the activation of NF-kappa B and, like the CLF-1/CLC heterodimer, promotes tyrosine phosphorylation of gp130, STAT3, and LIFR beta.^4-6 In addition, both recombinant CLC and the CLF-1/CLC heterodimer support the survival of embryonic neurons.⁶ CLC appears to be a much less potent mediator of neuron survival than the CLF-1/CLC heterodimer, however, suggesting that optimal biological activity of CLC may require dimerization with CLF-1.⁴ IL-12 p40 can form a homodimer, which blocks the binding of IL-12 to its receptor. CLF-1 can also homodimerize, but it is presently unknown whether or not CLF-1 can block CLF-1/CLC heterodimer or CNTF binding to the CNTFR complex.

References

1. Elson, G. et al. (1998) J. Immunology 161:1371.
2. Alexander, W. et al. (1999) Current Biology 9:605.
3. Lesser, S. and D. Lo (2000) Nature Neuroscience 3:851.
4. Elson, G. et al. (2000) Nature Neuroscience 3:867.
5. Shi, Y. et al. (1999) Biochem. Biophys. Res.Commun. 262:132.
6. Senaldi, G. et al. (1999) Proc. Natl. Acad. Sci. USA 96:11458.