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Vol. 19, Issue 1, 17-29, January 2008

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Protein Kinase C and Calmodulin Regulate Epidermal Growth Factor Receptor Recycling from Early Endosomes through Arp2/3 Complex and Cortactin

Anna Lladó^*,, Paul Timpson, Sandra Vilà de Muga^*, Jemina Moretó^*, Albert Pol^,||, Thomas Grewal^¶, Roger J. Daly, Carlos Enrich^*,, and Francesc Tebar^*

*Departament de Biologia Cel·lular, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036-Barcelona, Spain; Unitat de Microscopia Confocal, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Facultat de Medicina, Universitat de Barcelona, 08036-Barcelona, Spain; ^||Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010-Barcelona, Spain; ^¶Faculty of Pharmacy, University of Sydney, Sydney, NSW 2010, Australia; and The Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia

Submitted May 7, 2007; Revised October 4, 2007; Accepted October 12, 2007
Monitoring Editor: Adam Linstedt

The intracellular trafficking of the epidermal growth factor receptor (EGFR) is regulated by a cross-talk between calmodulin (CaM) and protein kinase C (PKC). On inhibition of CaM, PKC promotes the formation of enlarged early endosomes and blocks EGFR recycling and degradation. Here, we show that PKC impairs EGFR trafficking due to the formation of an F-actin coat surrounding early endosomes. The PKC-induced polymerization of actin is orchestrated by the Arp2/3 complex and requires the interaction of cortactin with PKC. Accordingly, inhibition of actin polymerization by using cytochalasin D or by overexpression of active cofilin, restored the normal morphology of the organelle and the recycling of EGFR. Similar results were obtained after down-regulation of cortactin and the sequestration of the Arp2/3 complex. Furthermore we demonstrate an interaction of cortactin with CaM and PKC, the latter being dependent on CaM inhibition. In summary, this study provides the first evidence that CaM and PKC organize actin dynamics in the early endosomal compartment, thereby regulating the intracellular trafficking of EGFR.

¹ To better visualize the actin cytoskeleton or due to the different efficiency of transfection or siRNA knockdown, we used the following cell lines: NRK, COS1, Vero, and HeLa. W13 or rottlerin have the same effect in all of the above-mentioned cell lines.

Address correspondence to: Carlos Enrich (enrich{at}ub.edu) or Francesc Tebar (tebar{at}ub.edu)