Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex.
Cardiotrophin-1 (CT-1) is a newly isolated cytokine that was identified based on its ability to induce cardiac myocyte hypertrophy. It is a member of the family of cytokines that includes interleukins-6 and -11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor, and oncostatin M. These cytokines induce a pleiotropic set of growth and differentiation activities via receptors that use a common signaling subunit, gp130. In this work we determine the activity of CT-1 in six in vitro biological assays and examine the composition of its cell surface receptor. We find that CT-1 is inactive in stimulating the growth of the hybridoma cell line, B9 and inhibits the growth of the mouse myeloid leukemia cell line, M1. CT-1 induces a phenotypic switch in rat sympathetic neurons and promotes the survival of rat dopaminergic and chick ciliary neurons. CT-1 also inhibits the differentiation of mouse embryonic stem cells. CT-1 and LIF cross-compete for binding to M1 cells, Kd [CT-1] approximately 0.7 nM, and this binding is inhibited by an anti-gp130 monoclonal antibody. Both ligands can be specifically cross-linked to a protein on M1 cells with the mobility of the LIF receptor (approximately 200 kDa). In addition, CT-1 binds directly to a purified, soluble form of the LIF receptor in solution (Kd approximately 2 nM). These data show that CT-1 has a wide range of hematopoietic, neuronal, and developmental activities and that it can act via the LIF receptor and the gp130 signaling subunit.
Pennica
D
D
Department of Molecular Biology, Genentech, Inc., South San Francisco, California 94080, USA.
Shaw
K J
KJ
Swanson
T A
TA
Moore
M W
MW
Shelton
D L
DL
Zioncheck
K A
KA
Rosenthal
A
A
Taga
T
T
Paoni
N F
NF
Wood
W I
WI
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D001681:Biological Assay; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D006131:Growth Inhibitors / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects; D066298:In Vitro Techniques; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008024:Ligands; D008222:Lymphokines / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D051381:Rats; D018121:Receptors, Cytokine / Q000378:metabolism*; D053606:Receptors, OSM-LIF; D015398:Signal Transduction
D016207:Cytokines; D017931:DNA Primers; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; C507842:Lifr protein, rat; D008024:Ligands; D008222:Lymphokines; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; C092073:cardiotrophin 1