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.

Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation / S. Sigismund, E. Argenzio, D. Tosoni, E. Cavallaro, S. Polo, P.P. Di Fiore. - In: DEVELOPMENTAL CELL. - ISSN 1534-5807. - 15:2(2008 Aug 12), pp. 209-219.

Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation

S. Sigismund;E. Argenzio
Secondo
;
S. Polo
Penultimo
;
P.P. Di Fiore
Ultimo
2008

Abstract

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.
EGFR ; endocytosis ; lipid rafts
Settore MED/04 - Patologia Generale
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/60017
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