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Sci. Signal., 22 December 2009
Vol. 2, Issue 102, p. ra84
[DOI: 10.1126/scisignal.2000576]


Regulation of Epidermal Growth Factor Receptor Trafficking by Lysine Deacetylase HDAC6

Yonathan Lissanu Deribe1, Philipp Wild1, Akhila Chandrashaker2, Jasna Curak3, Mirko H. H. Schmidt1,4, Yannis Kalaidzidis2,5, Natasa Milutinovic3, Irina Kratchmarova6, Lukas Buerkle3,7, Michael J. Fetchko3, Philipp Schmidt1, Saranya Kittanakom3, Kevin R. Brown8, Igor Jurisica8,9,10, Blagoy Blagoev6, Marino Zerial2, Igor Stagljar3*, and Ivan Dikic1,11,12*

1 Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University School of Medicine, Theodor-Stern-Kai 7, D-60590 Frankfurt (Main), Germany.
2 Max-Planck-Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
3 Departments of Biochemistry and Molecular Genetics, Terrence Donnelly Centre for Cellular and Biomolecular Research (CCBR), University of Toronto, 160 College Street, Room 1204, Toronto, Ontario, Canada M5S 3E1.
4 Laboratory for Tumor Biochemistry, Institute of Neurology (Edinger Institute), Goethe University School of Medicine, Heinrich-Hoffmann-Strasse 7, D-60528 Frankfurt (Main), Germany.
5 N. Belozersky Institute of Physico-Chemical Biology, Building A, Moscow State University, Moscow 119899, Russia.
6 Center for Experimental Bioinformatics, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense, Denmark.
7 Institute of Plant Science, ETH Zurich, CH-8092 Zurich, Switzerland.
8 Division of Signaling Biology, Ontario Cancer Institute, Princess Margaret Hospital–University Health Network, 101 College Street, Toronto Medical Discovery Tower, 9-305, Toronto, Ontario, Canada M5G 1L7.
9 Department of Computer Science, University of Toronto, Toronto, Ontario, Canada M5S 1A4.
10 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2M9.
11 Tumor Biology Program, Mediterranean Institute for Life Sciences, Mestrovicevo setaliste bb, 21000 Split, Croatia.
12 Department of Immunology, School of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia.

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 Tyr570 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.

* To whom correspondence should be addressed. E-mail: Ivan.Dikic{at} (I.D.) and igor.stagljar{at} (I.S.)

Citation: Y. Lissanu Deribe, P. Wild, A. Chandrashaker, J. Curak, M. H. H. Schmidt, Y. Kalaidzidis, N. Milutinovic, I. Kratchmarova, L. Buerkle, M. J. Fetchko, P. Schmidt, S. Kittanakom, K. R. Brown, I. Jurisica, B. Blagoev, M. Zerial, I. Stagljar, I. Dikic, Regulation of Epidermal Growth Factor Receptor Trafficking by Lysine Deacetylase HDAC6. Sci. Signal. 2, ra84 (2009).

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