title: Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
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.
authors.affiliation: Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University School of Medicine, Frankfurt (Main), Germany.
authors.forename: Yonathan Lissanu
authors.initials: YL
authors.lastname: Deribe
authors.forename: Philipp
authors.initials: P
authors.lastname: Wild
authors.forename: Akhila
authors.initials: A
authors.lastname: Chandrashaker
authors.forename: Jasna
authors.initials: J
authors.lastname: Curak
authors.forename: Mirko H H
authors.initials: MHH
authors.lastname: Schmidt
authors.forename: Yannis
authors.initials: Y
authors.lastname: Kalaidzidis
authors.forename: Natasa
authors.initials: N
authors.lastname: Milutinovic
authors.forename: Irina
authors.initials: I
authors.lastname: Kratchmarova
authors.forename: Lukas
authors.initials: L
authors.lastname: Buerkle
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fetchko
authors.forename: Philipp
authors.initials: P
authors.lastname: Schmidt
authors.forename: Saranya
authors.initials: S
authors.lastname: Kittanakom
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Brown
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.forename: Blagoy
authors.initials: B
authors.lastname: Blagoev
authors.forename: Marino
authors.initials: M
authors.lastname: Zerial
authors.forename: Igor
authors.initials: I
authors.lastname: Stagljar
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
mesh_terms: D000107:Acetylation; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D019295:Computational Biology; D066246:ErbB Receptors / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D012313:RNA / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014404:Tubulin / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D046912:Multiprotein Complexes; D014404:Tubulin; D012313:RNA; D066246:ErbB Receptors; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases