Signaling pathways recruited by the cardiotrophin-like cytokine/cytokine-like factor-1 composite cytokine: specific requirement of the membrane-bound form of ciliary neurotrophic factor receptor alpha component
| Autor: | E, Lelièvre, H, Plun-Favreau, S, Chevalier, J, Froger, C, Guillet, G C, Elson, J F, Gauchat, H, Gascan |
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| Rok vydání: | 2001 |
| Předmět: |
STAT3 Transcription Factor
MAP Kinase Signaling System Protein Tyrosine Phosphatase Non-Receptor Type 6 Intracellular Signaling Peptides and Proteins Protein Tyrosine Phosphatase Non-Receptor Type 11 Protein Serine-Threonine Kinases DNA-Binding Proteins STAT1 Transcription Factor Proto-Oncogene Proteins COS Cells Trans-Activators Tumor Cells Cultured Animals Cytokines Humans Protein Tyrosine Phosphatases Receptors Cytokine Proto-Oncogene Proteins c-akt Receptor Ciliary Neurotrophic Factor Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 276(25) |
| ISSN: | 0021-9258 |
| Popis: | Ciliary neurotrophic factor (CNTF) is a cytokine supporting the differentiation and survival of a number of neural cell types. Its receptor complex consists of a ligand-binding component, CNTF receptor (CNTFR), associated with two signaling receptor components, gp130 and leukemia inhibitory factor receptor (LIFR). Striking phenotypic differences between CNTF- and CNTFR-deficient mice suggest that CNTFR serves as a receptor for a second developmentally important ligand. We recently demonstrated that cardiotrophin-like cytokine (CLC) associates with the soluble orphan receptor cytokine-like factor-1 (CLF) to form a heterodimeric cytokine that displayed activities only on cells expressing the tripartite CNTF receptor on their surface. In this present study we examined the membrane binding of the CLC/CLF composite cytokine and observed a preferential interaction of the cytokine with the CNTFR subunit. Signaling pathways recruited by the CLC/CLF complex in human neuroblastoma cell lines were also analyzed in detail. The results obtained showed an activation of Janus kinases (JAK1, JAK2, and TYK2) leading to a tyrosine phosphorylation of the gp130 and LIFR. The phosphorylated signaling receptors served in turn as docking proteins for signal transducing molecules such as STAT3 and SHP-2. In vitro analysis revealed that the gp130-LIFR pathway could also stimulate the phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathways. In contrast to that reported before for CNTF, soluble CNTFR failed to promote the action CLC/CLF, and an absolute requirement of the membrane form of CNTFR was required to generate a functional response to the composite cytokine. This study reinforces the functional similarity between CNTF and the CLC/CLF composite cytokine defining the second ligand for CNTFR. |
| Databáze: | OpenAIRE |
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