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Mol Biol Cell. 2017 Oct 15;28(21):2802-2818. doi: 10.1091/mbc.E16-12-0871. Epub 2017 Aug 16.

Selective regulation of clathrin-mediated epidermal growth factor receptor signaling and endocytosis by phospholipase C and calcium.

Author information

1
Department of Chemistry and Biology and Graduate Program in Molecular Science, Ryerson University, Toronto, ON M5B 2K3, Canada.
2
Department of Chemistry and Biology and Graduate Program in Molecular Science, Ryerson University, Toronto, ON M5B 2K3, Canada cantonescu@ryerson.ca.
3
Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.

Abstract

Clathrin-mediated endocytosis is a major regulator of cell-surface protein internalization. Clathrin and other proteins assemble into small invaginating structures at the plasma membrane termed clathrin-coated pits (CCPs) that mediate vesicle formation. In addition, epidermal growth factor receptor (EGFR) signaling is regulated by its accumulation within CCPs. Given the diversity of proteins regulated by clathrin-mediated endocytosis, how this process may distinctly regulate specific receptors is a key question. We examined the selective regulation of clathrin-dependent EGFR signaling and endocytosis. We find that perturbations of phospholipase Cγ1 (PLCγ1), Ca2+, or protein kinase C (PKC) impair clathrin-mediated endocytosis of EGFR, the formation of CCPs harboring EGFR, and EGFR signaling. Each of these manipulations was without effect on the clathrin-mediated endocytosis of transferrin receptor (TfR). EGFR and TfR were recruited to largely distinct clathrin structures. In addition to control of initiation and assembly of CCPs, EGF stimulation also elicited a Ca2+- and PKC-dependent reduction in synaptojanin1 recruitment to clathrin structures, indicating broad control of CCP assembly by Ca2+ signals. Hence EGFR elicits PLCγ1-calcium signals to facilitate formation of a subset of CCPs, thus modulating its own signaling and endocytosis. This provides evidence for the versatility of CCPs to control diverse cellular processes.

PMID:
28814502
PMCID:
PMC5638584
DOI:
10.1091/mbc.E16-12-0871
[Indexed for MEDLINE]
Free PMC Article

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