Multiple Mechanisms Collectively Regulate Clathrin-Mediated Endocytosis of the Epidermal Growth Factor Receptor
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CitationGoh, Lai Kuan, Fangtian Huang, Woong Kim, Steven Gygi, and Alexander Sorkin. 2010. Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor. The Journal of Cell Biology 189, no. 5: 871-883.
AbstractEndocytosis of the epidermal growth factor receptor (EGFR) is important for the regulation of EGFR signaling. However, EGFR endocytosis mechanisms are poorly understood, which precludes development of approaches to specifically inhibit EGFR endocytosis and analyze its impact on signaling. Using a combination of receptor mutagenesis and RNA interference, we demonstrate that clathrin-dependent internalization of activated EGFR is regulated by four mechanisms, which function in a redundant and cooperative fashion. These mechanisms
involve ubiquitination of the receptor kinase domain, the clathrin adaptor complex AP-2, the Grb2 adaptor protein, and three C-terminal lysine residues (K1155, K1158, and K1164), which are acetylated, a novel posttranslational modification for the EGFR. Based on these findings, the first internalization-defective EGFR mutant with functional kinase and normal tyrosine phosphorylation was generated.
Analysis of the signaling kinetics of this mutant revealed that EGFR internalization is required for the sustained activation of protein kinase B/AKT but not for the activation of mitogenactivated protein kinase.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:5355108
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