One ubiquitin, 1000s of partners
24th November 2010 - Ubiquitin signals and ubiquitin-binding domains are implicated in almost every cellular process. But how is this wide spectrum of functionality achieved? How does ubiquitin find the correct target? Ivan Dikic and colleagues reviewed technological advances in monitoring the dynamics and specificity of ubiquitin networks in the journal Cell. Read more or listen to interview with Ivan Dikic.
Frankfurt researcher is admitted to the German Academy of Sciences
September 2010 - Ivan Dikic, member of the Cluster of Excellence Macromolecular Complexes (CEF) and the Scientific Director of the CEF-funded FMLS, is elected a member of the Leopoldina. The Leopoldina is Germany's National Academy that elects distinguished scientists from all over the world and advises the government on scientific issues and encourages an exchange of ideas with academies abroad and international scientists.
Dikic, who was born in Croatia, has earned recognition for his work on ubiquitin, a protein that - among other things - plays a role in carcinogenesis. He also received a € 2.5 million European Research Council “Advanced Investigator Grant”, a prestigious award that enables top European scientists to focus on innovative research projects. He will join the Biochemistry section of the Leopoldina.
Frankfurt University’s President Professor Werner Müller-Esterl congratulated his colleague, commenting that Ivan Dikic “wholeheartedly deserves this honour”. In accepting the accolade, Dikic said: “I am very honoured by this highly esteemed recognition and look forward to actively participating in Academy’s programmes, particularly in educational programmes and the popularisation of science”.
Contact for further information: Ms. Birgit Lipke, Institute of Biochemistry II, Niederrad Campus. Tel: +49 (0)69 6301-5652, or lipke@biochem2.de.
Digital Fly Embryo
July 2010 - CEF Investigator Ernst Stelzer and colleagues from the European Molecular Biology Laboratory in Heidelberg, the University of Heidelberg and the Sloan-Kettering Institute in New York have created the Fly Digital Embryo. In work reported on 4 July 2010 in the journal Nature Methods, they were able to film the development of fruit flys as well as that the eyes and midbrain of zebra fish.
Recording light-microscopy images of large, nontransparent specimens, such as developing multicellular organisms, is complicated by decreased contrast resulting from light scattering. Early zebrafish development can be captured by standard light-sheet microscopy, but new imaging strategies are required to obtain high-quality data of late development or of less transparent organisms. Ernst Stelzer and his team combined digital scanned laser light-sheet fluorescence microscopy with incoherent structured-illumination microscopy (DSLM-SI) and created structured-illumination patterns with continuously adjustable frequencies. The improved method discriminates the specimen-related scattered background from signal fluorescence, thereby removing out-of-focus light and optimizing the contrast of in-focus structures. DSLM-SI provides rapid control of the illumination pattern, exceptional imaging quality and high imaging speeds. The scientists conducted imaging of zebrafish development for 58 h and fast multiple-view imaging of early Drosophila melanogaster development. They reconstructed cell positions over time from the Drosophila DSLM-SI data and created a fly digital embryo. Their improvement in technique will help to shed light on processes and organisms, which have so far been under-studied because they could not be studied well under a microscope. All data, images and videos are freely available online, alongside the data from the digital embryo, at www.digital-embryo.org.
Full reference: Philipp J. Keller, Annette D. Schmidt, Anthony Santella, Khaled Khairy, Zhirong Bao, Joachim Wittbrodt and Ernst H.K. Stelzer. 2010. Fast, high-contrast imaging of animal development by scanned light sheet-based structured illumination microscopy. Nature Methods, 4 July 2010 (Advance Online Publication, DOI 10.1038/nmeth.1476). Link
New target for tumor therapy - Nature letter: When drugs could permanently disrupt the pathological formation of blood vessels
6th May 2010 - As from a specific size, solid tumors form a capillary network of blood vessels that grows along with them. One therapy approach is to suppress growth of blood vessels to starve the tumor. Drugs so far used in the clinic block the vessel growth factor VEGF (Vascular Endothelial Growth Factor). However, there is growing evidence that tumors can avoid or become resistant to this blockade. Little is known about how this takes place since the sprouting of blood vessels (angiogenesis) is not understood in detail yet. Prof. Amparo Acker-Palmer from the Cluster of Excellence Macromolecular complexes of the Goethe-University and her husband, Prof. Till Acker from the University of Giessen, now unraveled another signaling pathway in angiogenesis. As they report in the current issue of the journal “Nature”, these findings could reveal new targets for cancer therapy.
Notably, molecules that also arrange networks of neurons play a central role in this process. The neurobiologist Acker-Palmer has already intensively studied these so-called Ephrin-B2 receptors in conjunction with learning processes in the brain. For her work she was recently awarded with the Paul-Ehrlich price for young researchers. Now the scientist discovered that these receptors are present in the membrane of endothelial tip cells and are critical for angiogenesis. Ephrin-B2 not only transduces signals to neighboring cells by activating forward direction, but also reverse to the inside of the cell that expresses this ligands. Amparo Acker-Palmer and the neuropathologist Till Acker now deciphered a so far unknown signaling pathway downstream of ephrinb2 that regulates the internalization and activation of VEGFR2.
“As it turned out, the intracellular pathway that controls the internalization of the growth factor receptor constitutes an important mechanism required for angiogenesis”, Acker-Palmer explains the impact of her work. As a proof the two researchers blocked the cytoplasmic end of the ephrin-B2 ligand which transduces signals into the cell. In these animals, vessel sprouting was suppressed.
Apparently Ephrin-B2 regulates not only the growth factor receptor VEGFR2, which was so far suppressed by pharmaceuticals, but also another family member VEGFR3, as Ralf Adams and his colleagues of the Max-Planck-Institute for Molecular Biomedicine in Münster report in the same issue of Nature. “Ephrin-B2 thus is a crucial target for the development of pharmacological treatments that can prevent undesired blood vessel growth”, Till Acker explains.
Full reference: Suphansa Sawamiphak, Sascha Seidel, Clara L. Essmann, George A. Wilkinson, Mara E. Pitulescu, Till Acker & Amparo Acker-Palmer. 2010. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature. Online publication ahead of print 6 May 2010. doi:10.1038/nature08995. Link to full paper
Information: Prof. Amparo Acker-Palmer, Institute für Cell biology und Neuroscience, Frankfurt Institute for Molecular life Sciences, Campus Riedberg, Tel: (069) 798-29645; Acker-Palmer@bio.uni-frankfurt.de; Homepage of Amparo Acker-Palmer;
Speed limit for receptor trafficing in the cell
22nd December 2009 - 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.