Journal of Biological Chemistry
Volume 276, Issue 49, 7 December 2001, Pages 46204-46211
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MECHANISMS OF SIGNAL TRANSDUCTION
The Ribosomal S6 Kinases, cAMP-responsive Element-binding, and STAT3 Proteins Are Regulated by Different Leukemia Inhibitory Factor Signaling Pathways in Mouse Embryonic Stem Cells*

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Mouse embryonic stem (ES) cells remain “pluripotent” in vitro in the continuous presence of leukemia inhibitory factor (LIF). In the absence of LIF, ES cells are irreversibly committed to differentiate into various lineages. In this study we have set up an in vitro assay based on the anti-apoptotic activity of LIF to distinguish pluripotent from “differentiation-committed” ES cells. We have examined the phosphorylation profiles of known (STAT3 and ERKs) and identified new (ribosomal S6 kinases (RSKs) and cAMP-responsive element-binding protein (CREB)) LIF-regulated targets in ES and in ES-derived neuronal cells. We have demonstrated that although STAT3, a crucial player in the maintenance of ES cell pluripotency, is induced by LIF in all cell types tested, the LIF-dependent activation of RSKs is restricted to ES cells. We have shown that LIF-induced phosphorylation of RSKs in ES cells is dependent on ERKs, whereas STAT3 phosphorylation is not mediated by any known MAPK activities. Our results also demonstrate that the LIF-dependent phosphorylation of CREB is partially under the control of the RSK2 kinase.

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Published, JBC Papers in Press, October 1, 2001, DOI 10.1074/jbc.M106718200

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This work was supported by funds from the Center National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Center Hospitalier Universitaire Régional, the Association pour la Recherche sur le Cancer, the Ligue Nationale contre le Cancer, and the Université Louis Pasteur of Strasbourg.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.