Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation.
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.
Sigismund
Sara
S
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Via Adamello 16, 20139 Milan, Italy.
Argenzio
Elisabetta
E
Tosoni
Daniela
D
Cavallaro
Elena
E
Polo
Simona
S
Di Fiore
Pier Paolo
PP
D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D000818:Animals; D002966:Clathrin / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005372:Filipin / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D033962:Adaptor Protein Complex 2; D002966:Clathrin; D004815:Epidermal Growth Factor; D005372:Filipin; D066246:ErbB Receptors