Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
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.
Deribe
Yonathan Lissanu
YL
Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University School of Medicine, Frankfurt (Main), Germany.
Wild
Philipp
P
Chandrashaker
Akhila
A
Curak
Jasna
J
Schmidt
Mirko H H
MHH
Kalaidzidis
Yannis
Y
Milutinovic
Natasa
N
Kratchmarova
Irina
I
Buerkle
Lukas
L
Fetchko
Michael J
MJ
Schmidt
Philipp
P
Kittanakom
Saranya
S
Brown
Kevin R
KR
Jurisica
Igor
I
Blagoev
Blagoy
B
Zerial
Marino
M
Stagljar
Igor
I
Dikic
Ivan
I
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
D046912:Multiprotein Complexes; D014404:Tubulin; D012313:RNA; D066246:ErbB Receptors; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases