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J. Biol. Chem., Vol. 282, Issue 51, 37232-37243, December 21, 2007

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Modulation of F-actin Rearrangement by the Cyclic AMP/cAMP-dependent Protein Kinase (PKA) Pathway Is Mediated by MAPK-activated Protein Kinase 5 and Requires PKA-induced Nuclear Export of MK5^*

From the Department of Microbiology and Virology, Faculty of Medicine, University of Tromsø, N-9037 Tromsø, Norway

The MAPK-activated protein kinases belong to the Ca²⁺/calmodulin-dependent protein kinases. Within this group, MK2, MK3, and MK5 constitute three structurally related enzymes with distinct functions. Few genuine substrates for MK5 have been identified, and the only known biological role is in ras-induced senescence and in tumor suppression. Here we demonstrate that activation of cAMP-dependent protein kinase (PKA) or ectopic expression of the catalytic subunit C in PC12 cells results in transient nuclear export of MK5, which requires the kinase activity of both C and MK5 and the ability of C to enter the nucleus. C and MK5, but not MK2, interact in vivo, and C increases the kinase activity of MK5. Moreover, C augments MK5 phosphorylation, but not MK2, whereas MK5 does not seem to phosphorylate C. Activation of PKA can induce actin filament accumulation at the plasma membrane and formation of actin-based filopodia. We demonstrate that small interfering RNA-triggered depletion of MK5 interferes with PKA-induced F-actin rearrangement. Moreover, cytoplasmic expression of an activated MK5 variant is sufficient to mimic PKA-provoked F-actin remodeling. Our results describe a novel interaction between the PKA pathway and MAPK signaling cascades and suggest that MK5, but not MK2, is implicated in PKA-induced microfilament rearrangement.

Received for publication, June 13, 2007 , and in revised form, September 27, 2007.

^* This work was supported by grants from Norwegian Research Council Project S5228, Norwegian Cancer Society (Kreftforeningen) Project A01037, The Erna and Olav Aakres Foundation, and The Blix Family Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 47-776-44622; Fax: 47-776-45350; E-mail: ugom{at}fagmed.uit.no.

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