Cardiotrophin-1

doi:10.1074/jbc.270.18.10915

Cardiotrophin-1

BIOLOGICAL ACTIVITIES AND BINDING TO THE LEUKEMIA INHIBITORY FACTOR RECEPTOR/gp130 SIGNALING COMPLEX (*)

From the (1) Departments of Molecular Biology, Cell Genetics,
(2) Neurobiology,
(3) Immunology, and
(4) Cardiovascular Biology, Genentech, Inc., South San Francisco, California 94080 and the
(5) Institute for Molecular and Cellular Biology, Osaka University, Osaka 565, Japan

^§ To whom correspondence should be addressed. Tel.: 415-225-1221; Fax: 415-225-6127.

Abstract

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, K[CT-1] 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 (200 kDa). In addition, CT-1 binds directly to a purified, soluble form of the LIF receptor in solution (K 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.

Footnotes

↵* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

CT-1

cardiotrophin-1

IL

interleukin

LIF

leukemia inhibitory factor

CNTF

ciliary neurotrophic factor

OSM

oncostatin M

GPI

glycosyl-phosphatidylinositol

GPA

growth promoting activity

STAT

signal transducers and activators of transcription

SIE

c- sis-inducible element.
↵² M. Saito, T. Kishimoto, and T. Taga, manuscript in preparation.
↵³ While CT-1 is active in promoting the survival of ciliary neurons, it is 1000-fold less potent than CNTF (Fig. 2 C). Perhaps, this reduced potency is due to a greater species specificity of mouse CT-1 relative to rat CNTF for the chicken ciliary neuron assay. Differential species specificity has been proposed as the basis for the lack of activity of LIF in this system (70).