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J. Biol. Chem., Vol. 280, Issue 14, 13304-13314, April 8, 2005

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Functional Characterization of Human RSK4, a New 90-kDa Ribosomal S6 Kinase, Reveals Constitutive Activation in Most Cell Types^*

Bettina A. Dümmler¶, Camilla Hauge||, Joachim Silber, Helger G. Yntema**, Lars S. Kruse, Birte Kofoed, Brian A. Hemmings, Dario R. Alessi, and Morten Frödin||¶¶

From the Department of Clinical Biochemistry, Glostrup Hospital, 2600 Glostrup, Denmark, the ^**Department of Human Genetics, University Medical Centre St. Raboud, P. O. Box 9101, Nijmegen 6500 HB, the Netherlands, the Friedrich Miescher Institute, Maulbeerstrasse 66, CH-4558 Basel, Switzerland, Medical Research Council Protein Phosphorylation Unit, School of Life Sciences, Medical Sciences Institute/Wellcome Trust Biocentre Complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom, and the ^||Kinase Signalling Laboratory, Biotech Research and Innovation Centre, Fruebjergvej 3, 2100 Copenhagen Ø, Denmark

The 90-kDa ribosomal S6 kinases (RSK1–3) are important mediators of growth factor stimulation of cellular proliferation, survival, and differentiation and are activated via coordinated phosphorylation by ERK and 3-phosphoinositide-dependent protein kinase-1 (PDK1). Here we performed the functional characterization of a predicted new human RSK homologue, RSK4. We showed that RSK4 is a predominantly cytosolic protein with very low expression and several characteristics of the RSK family kinases, including the presence of two functional kinase domains and a C-terminal docking site for ERK. Surprisingly, however, in all cell types analyzed, endogenous RSK4 was maximally (constitutively) activated under serum-starved conditions where other RSKs are inactive due to their requirement for growth factor stimulation. Constitutive activation appeared to result from constitutive phosphorylation of Ser²³², Ser³⁷², and Ser³⁸⁹, and the low basal ERK activity in serum-starved cells appeared to be sufficient for induction of 50% of the constitutive RSK4 activity. Finally experiments in mouse embryonic stem cells with targeted deletion of the PDK1 gene suggested that PDK1 was not required for phosphorylation of Ser²³², a key regulatory site in the activation loop of the N-terminal kinase domain, that in other RSKs is phosphorylated by PDK1. The unusual regulation and growth factor-independent kinase activity indicate that RSK4 is functionally distinct from other RSKs and may help explain recent findings suggesting that RSK4 can participate in non-growth factor signaling as for instance p53-induced growth arrest.

Received for publication, July 20, 2004 , and in revised form, December 17, 2004.

^* The work was supported by grants from the Novo Nordisk Foundation (to M. F.), the Danish Medical Research Council (Grant No. 52-00-1162 to M. F.), the Danish Cancer Research Foundation (to M. F.), and the Krebsliga Schweiz (Grant KSF-01002-02-2000/OCS 1167-09-2001 to B. A. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this study.

^¶ Present address: The Friedrich Miescher Inst., Maulbeerstrasse 66, CH-4558 Basel, Switzerland.

^¶¶ To whom correspondence should be addressed: Biotech Research and Innovation Centre, Fruebjergvej 3, DK-2100 Copenhagen Ø, Denmark. E-mail: morten.frodin{at}bric.dk.

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