Regulation of Epidermal Growth Factor Receptor Trafficking by Lysine Deacetylase HDAC6
2009; American Association for the Advancement of Science; Volume: 2; Issue: 102 Linguagem: Inglês
10.1126/scisignal.2000576
ISSN1937-9145
AutoresYonathan Lissanu Deribe, Philipp S. Wild, Akhila Chandrashaker, Jasna Ćurak, Mirko H. H. Schmidt, Yannis Kalaidzidis, Natasa Milutinovic, Irina Kratchmarova, Lukas Buerkle, Michael J. Fetchko, Philipp Schmidt, Saranya Kittanakom, Kevin R. Brown, Igor Jurišica, Blagoy Blagoev, Marino Zerial, Igor Štagljar, Ivan Đikić,
Tópico(s)Ubiquitin and proteasome pathways
ResumoBinding 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.
Referência(s)