Regulation of Epidermal Growth Factor Receptor Trafficking by Lysine Deacetylase HDAC6

Yonathan Lissanu Deribe, Philipp Wild, Akhila Chandrashaker, Jasna Curak, Mirko H H Schmidt, Yannis Kalaidzidis, Natasa Milutinovic, Irina Kratchmarova, Lukas Buerkle, Michael J Fetchko, Philipp Schmidt, Saranya Kittanakom, Kevin R Brown, Igor Jurisica, Blagoy Blagoev, Marino Zerial, Igor Stagljar, Ivan Dikic

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Binding of epidermal growth factor (EGF) to its receptor leads to receptor dimerization, assembly of protein complexes, and activation of signaling networks that control key cellular responses. Despite their fundamental role in cell biology, little is known about protein complexes associated with the EGF receptor (EGFR) before growth factor stimulation. We used a modified membrane yeast two-hybrid system together with bioinformatics to identify 87 candidate proteins interacting with the ligand-unoccupied EGFR. Among them was histone deacetylase 6 (HDAC6), a cytoplasmic lysine deacetylase, which we found negatively regulated EGFR endocytosis and degradation by controlling the acetylation status of alpha-tubulin and, subsequently, receptor trafficking along microtubules. A negative feedback loop consisting of EGFR-mediated phosphorylation of HDAC6 Tyr(570) resulted in reduced deacetylase activity and increased acetylation of alpha-tubulin. This study illustrates the complexity of the EGFR-associated interactome and identifies protein acetylation as a previously unknown regulator of receptor endocytosis and degradation.
Original languageEnglish
JournalScience Signaling
Volume2
Issue number102
Pages (from-to)ra84
DOIs
Publication statusPublished - 1. Jan 2009

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