Protein kinase Cdelta and calmodulin regulate epidermal growth factor receptor recycling from early endosomes through Arp2/3 complex and cortactin.
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.
Lladó
Anna
A
Departament de Biologia Cellular, Facultat de Medicina, Universitat de Barcelona, Casanova 143, 08036-Barcelona, Spain.
Timpson
Paul
P
Vilà de Muga
Sandra
S
Moretó
Jemina
J
Pol
Albert
A
Grewal
Thomas
T
Daly
Roger J
RJ
Enrich
Carlos
C
Tebar
Francesc
F
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
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