Clathrin-Mediated Internalization Is Essential for Sustained EGFR Signaling but Dispensable for Degradation

Sara Sigismund, Elisabetta Argenzio, Daniela Tosoni, Elena Cavallaro, Simona Polo, Pier Paolo Di Fiore

Research output: Contribution to journalArticlepeer-review


Clathrin-mediated endocytosis (CME) is the major pathway of epidermal growth factor receptor (EGFR) internalization. It is commonly believed that CME mediates long-term attenuation of EGFR signaling by targeting the receptor for degradation. However, the EGFR can also be internalized through (a) clathrin-independent pathway(s), and it remains unclear why distinct mechanisms of internalization have evolved. Here, we report that EGFRs internalized via CME are not targeted for degradation, but instead are recycled to the cell surface. By contrast, clathrin-independent internalization preferentially commits the receptor to degradation. This finding has profound implications for signaling, as by skewing EGFR fate toward recycling rather than degradation, CME prolongs the duration of signaling. Our data show that CME determines the longevity of some EGFR-activated signaling pathways and that EGF-dependent biological responses, such as DNA synthesis, absolutely require CME. Thus, CME of the EGFR unexpectedly has a greater impact on receptor signaling than on receptor degradation.

Original languageEnglish
Pages (from-to)209-219
Number of pages11
JournalDevelopmental Cell
Issue number2
Publication statusPublished - Aug 12 2008



ASJC Scopus subject areas

  • Developmental Biology


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