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First published online May 4, 2004
doi: 10.1242/10.1242/jcs.01096

Journal of Cell Science 117, 2377-2388 (2004)
Published by The Company of Biologists 2004
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Research Article

PDE4-regulated cAMP degradation controls the assembly of integrin-dependent actin adhesion structures and REF52 cell migration

Yvonne M. Fleming1,2,*, Margaret C. Frame1,2 and Miles D. Houslay1

1 Institute of Biological and Life Sciences, Davidson and Wolfson Buildings, University of Glasgow, Glasgow G12 8QQ, UK
2 The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK

* Author for correspondence (e-mail: y.fleming{at}beatson.gla.ac.uk)

Accepted 9 January 2004

Plating of REF52 cells onto extracellular matrix components leads to the formation of integrin-dependent actin adhesion microspikes. We show that the formation of these structures is sensitive to chemical agents that regulate cAMP levels, such as forskolin and IBMX. In particular, by using the specific inhibitor rolipram, we identify the PDE4 family of cAMP-specific phosphodiesterases as critical regulators of this process. The effect of PDE4 on microspike formation is mediated by actions exerted through the activation of PKA – rather than through the alternative cAMP effector, Epac. We provide evidence that peripheral microspikes are RhoA-, ROCK- and myosin-dependent, and that this pathway is suppressed by PDE4 inhibition. In addition, PDE4 inhibition impairs cell locomotion that requires dynamic protrusion and retraction of peripheral spike structures. Our data demonstrate that PDE4 activity is a key modulator of integrin-induced actin assembly at the cell periphery which, in turn, controls cell migration.

Key words: Phosphodiesterase, Rolipram, Actin, RhoA


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