title: Protein kinase Cdelta and calmodulin regulate epidermal growth factor receptor recycling from early endosomes through Arp2/3 complex and cortactin.
abstract: The intracellular trafficking of the epidermal growth factor receptor (EGFR) is regulated by a cross-talk between calmodulin (CaM) and protein kinase Cdelta (PKCdelta). On inhibition of CaM, PKCdelta promotes the formation of enlarged early endosomes and blocks EGFR recycling and degradation. Here, we show that PKCdelta impairs EGFR trafficking due to the formation of an F-actin coat surrounding early endosomes. The PKCdelta-induced polymerization of actin is orchestrated by the Arp2/3 complex and requires the interaction of cortactin with PKCdelta. 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 PKCdelta, the latter being dependent on CaM inhibition. In summary, this study provides the first evidence that CaM and PKCdelta organize actin dynamics in the early endosomal compartment, thereby regulating the intracellular trafficking of EGFR.
authors.affiliation: Departament de Biologia Cellular, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036-Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Lladó
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.forename: Sandra
authors.initials: S
authors.lastname: Vilà de Muga
authors.forename: Jemina
authors.initials: J
authors.lastname: Moretó
authors.forename: Albert
authors.initials: A
authors.lastname: Pol
authors.forename: Thomas
authors.initials: T
authors.lastname: Grewal
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.forename: Carlos
authors.initials: C
authors.lastname: Enrich
authors.forename: Francesc
authors.initials: F
authors.lastname: Tebar
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D002147:Calmodulin / Q000378:metabolism*; D002460:Cell Line; D051356:Cortactin / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D011485:Protein Binding; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000378:metabolism
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D002147:Calmodulin; D051356:Cortactin; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D051745:Protein Kinase C-delta; D020743:rhoB GTP-Binding Protein