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MBC in Press, published online ahead of print October 24, 2007
Mol. Biol. Cell 10.1091/mbc.E07-05-0411

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Submitted on May 7, 2007
Revised on October 4, 2007
Accepted on October 12, 2007

PKC{delta} and Calmodulin Regulate EGF Receptor Recycling from Early Endosomes through Arp2/3 Complex and Cortactin

Anna Lladó,*{dagger} Paul Timpson,{ddagger} Sandra Vilà de Muga,* Jemina Moretó,* Albert Pol,{sect} Thomas Grewal,|| Roger J. Daly,{ddagger} Carlos Enrich,* and Francesc Tebar*

*Departament de Biologia Cellular and {dagger}Unitat de Microscopia Confocal, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain; {sect}Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; ||Centre for Immunology, St. Vincent’s Hospital, University of New South Wales; {ddagger}The Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia

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-delta (PKC{delta}). On inhibition of CaM, PKC{delta} promotes the formation of enlarged early endosomes and blocks EGFR recycling and degradation. Here we show that PKC{delta} impairs EGFR trafficking due to the formation of an F-actin coat surrounding early endosomes. The PKC{delta}-induced polymerization of actin is orchestrated by the Arp2/3 complex and requires the interaction of cortactin with PKC{delta}. Accordingly, inhibition of actin polymerization utilizing 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{delta}, the latter being dependent on CaM inhibition. In summary, this study provides the first evidence that CaM and PKC{delta} organize actin dynamics in the early endosomal compartment, thereby regulating the intracellular trafficking of EGFR.

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






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