Molecularly Distinct Clathrin-Coated Pits Differentially Impact EGFR Fate and Signaling

Roberta Pascolutti, Veronica Algisi, Alexia Conte, Andrea Raimondi, Mithun Pasham, Srigokul Upadhyayula, Raphael Gaudin, Tanja Maritzen, Elisa Barbieri, Giusi Caldieri, Chiara Tordonato, Stefano Confalonieri, Stefano Freddi, Maria Grazia Malabarba, Elena Maspero, Simona Polo, Carlo Tacchetti, Volker Haucke, Tom Kirchhausen, Pier Paolo Di FioreSara Sigismund

Research output: Contribution to journalArticle

Abstract

Adaptor protein 2 (AP2) is a major constituent of clathrin-coated pits (CCPs). Whether it is essential for all forms of clathrin-mediated endocytosis (CME) in mammalian cells is an open issue. Here, we demonstrate, by live TIRF microscopy, the existence of a subclass of relatively short-lived CCPs lacking AP2 under physiological, unperturbed conditions. This subclass is retained in AP2-knockout cells and is able to support the internalization of epidermal growth factor receptor (EGFR) but not of transferrin receptor (TfR). The AP2-independent internalization mechanism relies on the endocytic adaptors eps15, eps15L1, and epsin1. The absence of AP2 impairs the recycling of the EGFR to the cell surface, thereby augmenting its degradation. Accordingly, under conditions of AP2 ablation, we detected dampening of EGFR-dependent AKT signaling and cell migration, arguing that distinct classes of CCPs could provide specialized functions in regulating EGFR recycling and signaling. EGFR signaling controls different cell physiological processes, including proliferation and migration. Pascolutti et al. describe an additional layer of regulation of EGFR signaling, relying on the sequestration of receptors into molecularly distinct clathrin-coated vesicles that regulate receptor fate toward recycling versus degradation, with impact on the final cellular output.

Original languageEnglish
Pages (from-to)3049-3061.e6
JournalCell Reports
Volume27
Issue number10
DOIs
Publication statusPublished - Jun 4 2019

Keywords

  • AP2
  • clathrin-coated pits
  • EGFR
  • endocytic adaptors
  • endocytosis
  • eps15
  • epsin
  • receptor degradation
  • recycling
  • signaling
  • transcription

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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