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Vol. 20, Issue 14, 3209-3223, July 15, 2009

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Cortactin Promotes Migration and Platelet-derived Growth Factor-induced Actin Reorganization by Signaling to Rho-GTPases

Frank P.L. Lai^*,, Malgorzata Szczodrak^*,, J. Margit Oelkers^*,, Markus Ladwein^*, Filippo Acconcia^,||, Stefanie Benesch^¶, Sonja Auinger^¶, Jan Faix^#, J. Victor Small^¶, Simona Polo, Theresia E.B. Stradal^@, and Klemens Rottner^*

*Cytoskeleton Dynamics Group, ^@Signalling and Motility Group, Helmholtz Centre for Infection Research, D-38124 Braunschweig, Germany; IFOM Foundation, The FIRC Institute for Molecular Oncology, 20139 Milan, Italy; ^¶Institute of Molecular Biotechnology, Austrian Academy of Sciences, A-1030 Vienna, Austria; and ^#Institute for Biophysical Chemistry, Hannover Medical School, D-30625 Hannover, Germany

Submitted December 8, 2008; Revised May 5, 2009; Accepted May 11, 2009
Monitoring Editor: David G. Drubin

Dynamic actin rearrangements are initiated and maintained by actin filament nucleators, including the Arp2/3-complex. This protein assembly is activated in vitro by distinct nucleation-promoting factors such as Wiskott-Aldrich syndrome protein/Scar family proteins or cortactin, but the relative in vivo functions of each of them remain controversial. Here, we report the conditional genetic disruption of murine cortactin, implicated previously in dynamic actin reorganizations driving lamellipodium protrusion and endocytosis. Unexpectedly, cortactin-deficient cells showed little changes in overall cell morphology and growth. Ultrastructural analyses and live-cell imaging studies revealed unimpaired lamellipodial architecture, Rac-induced protrusion, and actin network turnover, although actin assembly rates in the lamellipodium were modestly increased. In contrast, platelet-derived growth factor-induced actin reorganization and Rac activation were impaired in cortactin null cells. In addition, cortactin deficiency caused reduction of Cdc42 activity and defects in random and directed cell migration. Reduced migration of cortactin null cells could be restored, at least in part, by active Rac and Cdc42 variants. Finally, cortactin removal did not affect the efficiency of receptor-mediated endocytosis. Together, we conclude that cortactin is fully dispensable for Arp2/3-complex activation during lamellipodia protrusion or clathrin pit endocytosis. Furthermore, we propose that cortactin promotes cell migration indirectly, through contributing to activation of selected Rho-GTPases.

These authors contributed equally to this work.

Present addresses: Department of Developmental and Regenerative Biology, Institute of Medical Biology, 8A Biomedical Grove, 06-06 Immunos, Singapore 138648;

^|| Department of Biology, University ROMA TRE, Viale G. Marconi 446, I-00146 Rome, Italy.

Address correspondence to: Klemens Rottner (klemens.rottner{at}helmholtz-hzi.de)