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Cloning and characterization of a specific receptor for mouse oncostatin M
R A Lindberg1, T S Juan, A A Welcher
1Department of Immunology, Amgen, Inc., Thousand Oaks, California 91320-1789, USA.
Abstract:
Oncostatin M (OSM) is a member of a family of cytokines that includes ciliary neurotrophic factor, interleukin-6, interleukin-11, cardiotrophin-1, and leukemia inhibitory factor (LIF). The receptors for these cytokines consist of a common signaling subunit, gp130, to which other subunits are added to modify ligand specificity. We report here the isolation and characterization of a cDNA encoding a subunit of the mouse OSM receptor. In NIH 3T3 cells (which endogenously express gp130, LIF receptor beta [LIFRbeta], and the protein product, c12, of the cDNA described here), mouse LIF, human LIF, and human OSM signaled through receptors containing the LIFRbeta and gp130 but not through the mouse OSM receptor. Mouse OSM, however, signaled only through a c12-gp130 complex; it did not use the LIF receptor. Binding studies demonstrated that mouse OSM associated directly with either the c12 protein or gp130. These data highlight the species-specific differences in receptor utilization and signal transduction between mouse and human OSM. In mouse cells, only mouse OSM is capable of activating the mouse OSM receptor; human OSM instead activates the LIF receptor. Therefore, these data suggest that all previous studies with human OSM in mouse systems did not elucidate the biology of OSM but, rather, reflected the biological actions of LIF.
Insights
Mouse Oncostatin M (OSM) signals through a specific receptor, distinct from the one used by human OSM in mouse cells. This finding clarifies species-specific cytokine receptor interactions and signaling pathways.
Area of Science:
- Cytokine signaling
- Receptor biology
- Immunology
Background:
- Oncostatin M (OSM) belongs to a cytokine family that shares the gp130 signaling subunit.
- Ligand specificity is determined by additional receptor subunits.
- Understanding OSM receptor interactions is crucial for deciphering its biological roles.
Purpose of the Study:
- To isolate and characterize the cDNA encoding a subunit of the mouse OSM receptor.
- To investigate the species-specific differences in OSM receptor utilization and signal transduction between mouse and human OSM.
- To clarify the signaling pathways of mouse and human OSM in mouse cells.
Main Methods:
- Isolation and characterization of a cDNA encoding a mouse OSM receptor subunit (c12).
- Expression analysis in NIH 3T3 cells.
- Ligand binding studies with mouse and human OSM, and mouse/human LIF.
- Signal transduction assays.
Main Results:
- Mouse OSM signals exclusively through a c12-gp130 receptor complex in mouse cells.
- Human OSM and LIF signal through LIF receptor beta (LIFRbeta)-gp130 complexes in mouse cells, not the mouse OSM receptor.
- Mouse OSM directly binds to the c12 protein or gp130.
- Species-specific receptor usage was confirmed: mouse OSM activates the mouse OSM receptor, while human OSM activates the LIF receptor in mouse cells.
Conclusions:
- Mouse and human OSM exhibit species-specific receptor utilization and signal transduction.
- Previous studies using human OSM in mouse models likely reflected LIF signaling, not true OSM biology.
- The identified c12 subunit is critical for mouse OSM-specific signaling.