Journal
SCIENCE SIGNALING
Volume 2, Issue 102, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2000576
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Funding
- Deutsche Forschungsgemeinschaft
- Goethe University Frankfurt [EXC115]
- Canadian Foundation for Innovation (CFI)
- Canadian Institute for Health Research (CIHR)
- Canadian Cancer Society Research Institute (CCSRI)
- Canadian Heart and Stroke Foundation
- Genentech
- Novartis
- Genome Canada through Ontario Genomics Institute
- Canada Foundation for Innovation
- IBM
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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.
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