CT-1 Receptor Kenneth R. Chien* Department of Medicine, Center for Molecular Genetics, and the American Heart Association-Bugher Foundation, Center for Molecular Biology, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA * corresponding author tel: 619 534 6835, fax: 619 534 8081, e-mail:
[email protected] DOI: 10.1006/rwcy.2000.17006.
SUMMARY
Structure
The CT-1 ligand receptor system has not been fully elucidated. This notion should be advanced by the molecular cloning of the CT-1-specific receptor.
See chapters on gp130 (IL-6 receptor) and LIFR.
BACKGROUND
Discovery Cardiotropin 1, CT-1, signals via heterodimerization of the gp130 (IL-6 receptor) and LIF receptors (LIFR) (Pennica et al., 1995; Wollert et al., 1996). The subsequent activation events reveal that CT-1 induces and utilizes JAK1-, JAK2-, and TYK2associated tyrosine kinases, which are in turn relayed by signaling via the STAT3 transcription factor (Robledo et al., 1997). Crosslinking of iodinated CT-1 to the cell surface led to the identification of a third component in addition to gp130 and LIFR, with an apparent molecular mass of 80 kDa. On motor neurons, CT-1 action was inhibited by phosphatidylinositol-specific phospholipase C, suggesting that CT-1 may act through a GPI-linked component. Since no binding of CT-1 to ciliary neurotropic factor receptor (CNTFR; GPI-linked receptor) was detected, CT-1 may use a novel cytokine receptor subunit (Pennica et al., 1996). Thus, a CT-1-specific receptor subunit has been proposed, but thus far not verified by molecular cloning of the corresponding cDNA.
Main activities and pathophysiological roles See chapter on CT-1.
GENE
Accession numbers See chapters on gp130 (IL-6 receptor) and LIFR. A CT-1-specific receptor gene has not been cloned.
Sequence See chapters on gp130 (IL-6 receptor) and LIFR.
Chromosome location and linkages See chapters on gp130 (IL-6 receptor) and LIFR.
PROTEIN
Alternative names
Accession numbers
gp130, LIFR.
See chapters on gp130 (IL-6 receptor) and LIFR.
1814 Kenneth R. Chien
Description of protein
Release of soluble receptors
See chapters on gp130 (IL-6 receptor) and LIFR. Crosslinking of iodinated CT-1 to the cell surface led to the identification of a third component in addition to gp130 and LIFR, with an apparent molecular mass of 80 kDa. Removal of N-linked carbohydrates from the protein backbone of the third component resulted in a protein of 45 kDa. On motor neurons, CT-1 action was inhibited by phosphatidylinositol-specific phospholipase C, suggesting that CT-1 may act through a GPI-linked component (Pennica et al., 1996) (see chapter on CNTF receptor).
See chapters on gp130 (IL-6 receptor) and LIFR.
SIGNAL TRANSDUCTION
Associated or intrinsic kinases CT-1 induces the rapid tyrosine phosphorylation of gp130 and LIFR, leading to the activation of JAK1, JAK2, and TYK2 kinase, as reported for the other members of the IL-6 cytokine family (Wollert et al., 1996; Robledo et al., 1997).
Relevant homologies and species differences
Cytoplasmic signaling cascades
See chapters on gp130 (IL-6 receptor) and LIFR.
See section on In vitro activities in the chapter on CT-1.
Affinity for ligand(s) Binding studies employing purified soluble gp130 and LIFR molecules demonstrate that CT-1 binds to the LIFR with about the same affinity as LIF but fails to bind to gp130 alone; however, the addition of gp130 enhanced the binding of CT-1 to the LIFR (Pennica et al., 1995). Therefore CT-1 receptor binding involves an initial low-affinity interaction with the LIFR, followed by the recruitment of gp130 into a highaffinity heterotrimeric complex (Pennica et al., 1995).
Cell types and tissues expressing the receptor See the chapters on gp130 (IL-6 receptor) and LIFR. Functional studies and receptor-binding studies in cultured cardiomyocytes and the mouse myeloid leukemia cell line M1 have revealed that CT-1 signals through the gp130/LIFR heterodimer in cardiomyocytes, most likely without a further requirement for a specific receptor (Pennica et al., 1995, 1996; Wollert et al., 1996). By contrast, CT-1 signaling in neuronal cells may require an additional CT-1-specific receptor (Pennica et al., 1996; Robledo et al., 1997).
Regulation of receptor expression See chapters on gp130 (IL-6 receptor) and LIFR.
DOWNSTREAM GENE ACTIVATION
Transcription factors activated See section on In vitro activities in the chapter on CT-1.
Genes induced See section on In vitro activities in the chapter on CT-1.
Promoter regions involved See the chapters on gp130 (IL-6 receptor) and LIFR.
BIOLOGICAL CONSEQUENCES OF ACTIVATING OR INHIBITING RECEPTOR AND PATHOPHYSIOLOGY
Unique biological effects of activating the receptors See section on In vivo biological activities of ligands in animal models in the chapter on CT-1.
CT-1 Receptor 1815
References Pennica, D., Shaw, K. J., Swanson, T. A., Moore, M. W., Shelton, D. L., Zioncheck, K. A., Rosenthal, A., Taga, T., Paoni, N. F., and Wood, W. I. (1995). Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J. Biol. Chem. 270, 10915±10922. Pennica, D., Arce, V., Swanson, T. A., Vejsada, R., Pollock, R. A., Armanini, M., Dudley, K., Phillips, H. S., Rosenthal, A., Kato, A. C., and Henderson, C. E. (1996). Cardiotrophin-1, a cytokine present in embryonic muscle, supports long-term survival of spinal motoneurons. Neuron 17, 63±74. Robledo, O., Fourcin, M., Chevalier, S., Guillet, C., Auguste, P., Pouplard-Barthelaix, A., Pennica, D., and Gascan, H. (1997).
Signaling of the cardiotrophin-1 receptor. Evidence for a third receptor component. J. Biol. Chem. 272, 4855±4863. Wollert, K. C., Taga, T., Saito, M., Narazaki, M., Kishimoto, T., Glembotski, C. C., Vernallis, A. B., Heath, J. K., Pennica, D., Wood, W. I., and Chien, K. R. (1996). Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathways. J. Biol. Chem. 271, 9535±9545.
LICENSED PRODUCTS See the chapters on gp130 (IL-6 Receptor) and LIF Receptor.
