Signaling of the cardiotrophin-1 receptor. Evidence for a third receptor component.
Cardiotrophin-1 (CT-1) is a recently isolated cytokine belonging to the interleukin-6 cytokine family. In the present study we show that CT-1 activates its receptor expressed at the surface of a human neural cell line by recruiting gp130 and gp190/leukemia inhibitory factor receptor beta, as shown by analyzing their tyrosine phosphorylation level. Neutralizing antibody directed against gp130 and reconstitution experiments performed in the COS-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for CT-1 signaling. Analysis of the subsequent activation events revealed that CT-1 induces and utilizes Jak1-, Jak2-, and Tyk2-associated tyrosine kinases, which are in turn relayed by STAT-3 transcription factor. Cross-linking of iodinated CT-1 to the cell surface led to the identification of a third alpha component in addition to gp130 and gp190, with an apparent molecular mass of 80 kDa. Removal of N-linked carbohydrates from the protein backbone of the alpha component resulted in a protein of 45 kDa. Our results provide evidence that the CT-1 receptor is composed of a tripartite complex, a situation similar to the high affinity receptor for ciliary neurotrophic factor.
Robledo
O
O
Laboratoire de Biologie Cellulaire, 4 rue Larrey, CHU Angers, 49033 Angers Cedex, France.
Fourcin
M
M
Chevalier
S
S
Guillet
C
C
Auguste
P
P
Pouplard-Barthelaix
A
A
Pennica
D
D
Gascan
H
H
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000378:metabolism*; D018014:Gene Transfer Techniques; D006131:Growth Inhibitors; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D053606:Receptors, OSM-LIF; D015398:Signal Transduction
D015703:Antigens, CD; D016207:Cytokines; D006131:Growth Inhibitors; C494199:IL6ST protein, human; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D008562:Membrane Glycoproteins; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050822:Cytokine Receptor gp130; C092073:cardiotrophin 1