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J. Biol. Chem., Vol. 280, Issue 43, 35844-35858, October 28, 2005

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Regulation of Microfilament Organization by Kaposi Sarcoma-associated Herpes Virus-cyclin·CDK6 Phosphorylation of Caldesmon^*

Maria Emanuela Cuomo1, Axel Knebel¶, Georgina Platt, Nick Morrice, Philip Cohen, and Sibylle Mittnacht2

From the Cancer Research UK Centre for Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research, 237 Fulham Road, SW3 6JB London, United Kingdom, MRC Protein Phosphorylation Unit, University of Dundee, MSI/WTB Complex, Dow Street, DD1 5EH Dundee, United Kingdom, and ^¶Kinasource, Laboratory 4.21, MSI/WTB Complex, Dow Street, DD1 5EH Dundee, United Kingdom

Kaposi sarcoma-associated herpes virus (KSHV) encodes a D-like cyclin (K-cyclin) that is thought to contribute to the viral oncogenicity. K-cyclin activates cellular cyclin-dependent kinases (CDK) 4 and 6, generating enzymes with a substrate selectivity deviant from CDK4 and CDK6 activated by D-type cyclins, suggesting different biochemical and biological functions. Here we report the identification of the actin- and calmodulin-binding protein caldesmon (CALD1) as a novel K-cyclin·CDK substrate, which is not phosphorylated by D·CDK. CALD1 plays a central role in the regulation of microfilament organization, consequently controlling cell shape, adhesion, cytokinesis and motility. K-cyclin·CDK6 specifically phosphorylates four Ser/Thr sites in the human CALD1 carboxyl terminus, abolishing CALD1 binding to its effector protein, actin, and its regulator protein, calmodulin. CALD1 is hyperphosphorylated in cells following K-cyclin expression and in KSHV-transformed lymphoma cells. Moreover, expression of exogenous K-cyclin results in microfilament loss and changes in cell morphology; both effects are reliant on CDK catalysis and can be reversed by the expression of a phosphorylation defective CALD1. Together, these data strongly suggest that K-cyclin expression modulates the activity of caldesmon and through this the microfilament functions in cells. These results establish a novel link between KSHV infection and the regulation of the actin cytoskeleton.

Received for publication, April 11, 2005 , and in revised form, August 5, 2005.

^* This work was funded by grants from Cancer Research UK (to S. M. and G. P.) and the Medical Research Council (A. K., N. M., and P. C.). 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 material.

¹ Recipient of an Institute of Cancer Research Ph.D. scholarship.

² To whom correspondence should be sent. Tel.: 44-20-7878-3859; Fax: 44-20-7352-3299; E-mail: sibylle{at}icr.ac.uk.

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