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Speed limit for receptor trafficing in the cell
Protein acetylation inhibits effects of growth factors
22 December 2009 - FRANKFURT. For research focused on cancer it is important to understand the regulation of growth factors which are responsible for the proliferation and differentiation of cells. Growth hormones signal to the cell via receptors that are positioned in the cell membrane. When an extracellular growth factor docks on its receptor, the membrane area surrounding it invaginates and gets cut off. Enclosed in a small bubble (vesicel) inside the cell the receptor is transported to other membrane enclosed compartments where it can signal to the cell to proliferate or to migrate. The receptor can also be silenced on the other hand by transporting it to the lysosome where it gets degraded. To understand the regulation of these two opposing processes, an international collaboration of researchers with major impacts by scientists from the Goethe University systematically searched for proteins that interact with the so called EGF-receptor. They found out that an enzyme, responsible for the transport of the receptor seems to play a key role in this regulation.
The epidermal growth factor (EGF) plays a crucial role in the onset of cell proliferation. It acts by binding to a class of receptors which are known as EGF receptors (EGFR). An initial systematic computer-based screen for the identification of EGFR interacting proteins revealed 87 proteins; one of which was HDAC6. This enzyme is able to influence the transport of EGFR containing vesicles along microtubules within the cell.
„Since my start as an independent scientist I have been fascinated by complexity and dynamics of receptor trafficking inside the cell“ explains Prof. Ivan Dikic from the Institute of Biochemistry II, Goethe-University. „This process is reminiscent of the complex train system in Europe, having multiple layers of control, train system and connections“. Previous work by his group has shown that receptor phosphorylation and ubiquitylation control this process. Together with collaborators from Canada the latest work expands the repertoire of regulation by reversible protein acetylation. HDAC6 removes acetyl groups from -tubulin, the building unit of microtubules, and slows down the trafficking events in cells, e.g. transport of EGFR containing vesicles.
Phosphorylation of HDAC6, which decreases its activity, by activated EGFR creates a negative feedback loop, whereby -tubulin remaining acetylated increases the rate of delivery of EGFR to lysosomes. „These insights might be instrumental in the treatment of cancer“ states a PhD student Yonathan Lissanu Deribe from Adis Abeba, Ethiopia. He came to Germany to do his PhD thesis in the group of Prof. Ivan Dikic which he is about to leave for a postdoctoral training in Boston. „Since EGFRs are frequently deregulated in human tumors (e.g. head and neck, glioblastoma and others) a combinatorial therapy inhibiting both the EGFR and HDAC6 could have beneficial effects for treating these types of cancer“.
This work is an excellent example of combination of modern technologies, high-through put screens and bioinformatics with hypothesis driven cellular and molecular biology research. The success of this project is a multidisciplinary and multinational collaborative network including groups from the Institute of Biochemistry II and Edinger Institute of the Goethe-University, the Frankfurt Cluster of Excellence „Macromolecular Complexes“, the Max-Planck-Institute of Molecular Cell Biology and Genetics in Dresden, the Center for Experimental Bioinformatics of the University of Odense in Denmark and two groups at the University of Toronto.
Link to the research publication in Science Signaling
Full reference: Lissanu Deribe Y, Wild P, Chandrashaker A, Curak J, Schmidt MHH, Kalaidzidis Y, Milutinovic N, Kratchmarova I, Buerkle L, Fetchko MJ, Schmidt P, Kittanakom S, Brown KR, Jurisica I, Blagoev B, Zerial M, Stagljar I, Dikic I (2009) Regulation of Epidermal Growth Factor Receptor Trafficking by Lysine Deacetylase HDAC6. Sci Signal 2:ra84