Biographie

Prof. Robin Ketteler studierte Biochemie mit Diplom an der Freien Universität Berlin, bevor er seine Doktorarbeit am Max-Planck Institut für Immunbiologie in Freiburg zum Thema “Signaltransduktionskaskaden des Erythropoetinrezeptor” mit summa cum laude abschloß. Anschliessend erforschte er die Signalleitung des EGF Rezeptors am Massachusetts General Hospital in Boston, USA, bevor er seine eigene Arbeitsgruppe am University College London zum Thema “Autophagie und Signaltransduktion” startete.  Darüber hinaus etablierte Dr. Ketteler am University College London die erste High-Content Screening facility für systematisches Screening mit chemischen Molekülen, siRNA und CRISPR guide Libraries. Im Jahre 2019 erhielt er die volle Professur für Translationale Zellbiologie am University College London, wo er immer noch als Honorary Professor eingeschrieben ist. Seit 2022 ist Dr. Robin Ketteler Professor für Biochemie an der Medical School Berlin.  

Biography

Prof. Robin Ketteler studied Biochemistry at the Free University Berlin and completed his PhD thesis at the Max-Planck Institute for Immunobiology in Freiburg, working on signaling cascades of the Erythropoietin receptor in hematopoietic progenitor cells. He then studied cell signaling at the Massachusetts General Hospital in Boston, using high-content imaging and systems biology approaches. In 2009, Dr. Ketteler established his research group at University College London with main aims to investigate autophagy and cell signalling. In addition, Dr. Ketteler established the first high-content screening facility at UCL, focussing on systematic screening of small molecules, siRNA and CRISPR guideRNA libraries. In 2019, he was appointed as full Professor for Translational Cell Biology at University College London. In 2022, he was appointed as Professor for Biochemistry at the Medical School Berlin.  

Lehrtätigkeit 

Prof. Ketteler hat eine langjährige Erfahrung in der Lehre am University College London erlangt, wo er vor allem Masters Studenten in Drug Design und Biochemie unterrichtet hat. Diese Lehrtätigkeit setzt Herr Ketteler nun an der Medical School Berlin fort und unterrichtet Medizinstudenten im 2. – 4. Semester, u.a. in den Fächern Biochemie, Immunologie und Molekulare Medizin. Dr. Ketteler hat 5 Doktoranden (PhD) an UCL als Erstbetreuer betreut und über 30 Masters Studenten zu einer erfolgreichen Abschlussarbeit geführt. 

Teaching

Prof. Ketteler has a long experience in teaching undergraduate and Masters students at University College London, in the area of Drug Design and Biochemistry. He will continue his teaching responsibilities at the Medical School Berlin, teaching lectures and seminars for 2^nd to 4^th Semester medical students in the topics of biochemistry, immunology and molecular medicine, among others. Prof. Ketteler has supervised 5 PhD students and over 30 Masters students at UCL as primary supervisor. 

Forschung

Das Ketteler Labor untersucht das Wachstum und die Signaltransduktion von gesunden und entarteten Zellen. Ein Hauptziel ist es, neue therapeutische Ansätze zu entwickeln, welche den Prozess der Autophagie angreifen. Wir benutzen Systembiologie und Chemische Biologie, um zentrale Mechanismen der Autophagie in der Krebsentstehung zu entdecken. 

Ein Schwerpunkt unserer Forschung liegt auf der Protease ATG4B, welche eine zentrale Rolle in der Bildung des Autophagosoms hat. Wir haben mehrere ATG4 Knockout Zelllinien etabliert, um post-translationale Mechanismen der ATG4 Regulation zu erforschen. Dabei haben wir eine neuartige post-translationale Regulation entdeckt, die ATG8-ylierung (Abbildung 1). In unserer momentanen Forschung versuchen wir, die molekularen Mechanismen der ATG8-ylierung im Detail zu verstehen und die Relevanz dieser Modifizierung bei zellulären Prozessen zu begreifen. Darüber hinaus setzen wir unsere translationale Forschung fort, um hochselektive Inhibitoren für ATG4B und die Autophagie zu entwickeln und Methoden für CRISPR-basiertes Screening zu entwickeln (Abbildung 2). 

Abbildung 1: Die Protease ATG4B reguliert die LC3-ylierung (auch ATG8-ylierung genannt) von Zielproteinen. Die LC3-ylierung ist eine neuartige post-translationale Modifikation, die das Ketteler Labor entdeckt hat und welche noch nicht gut verstanden ist. Links: schematische Darstellung der LC3-ylierung von ATG3 an Lysine K243. Rechts: Modell der LC3-ylierung von ATG3. LC3B in gelb, ATG3 in blau. Quelle: Agrotis et al. J Biol Chem 2019; Modelling: Nivedita Singh).

Abbildung 2: Use of CRISPR/Cas9 for high-throughput screening. CRISPR screening can be done either in a pooled format (A) or in an arrayed format (B). In pooled screening, the output is determined by sequencing of guideRNAs integrated in genomic DNA and requires selection of cells. In arrayed format, the hits are defined by selection of phenotypes. Adapted from Agrotis and Ketteler, Frontiers in Genetics 2015.

Research

The Ketteler lab focusses on understanding processes that control cell growth and signaling in health and disease. A key aim is to develop therapeutic opportunities targeting the autophagy pathway in cancer and neurodegeneration. My lab is using systems biology and chemical biology approaches such as CRISPR genome editing and small molecule compound screening to pursue early drug discovery strategies. The long-term goal is to identify specific key nodes in the pathway that can be modulated small molecule compounds to develop drug therapies for diseases such as cancer and neurodegeneration.

We have previously studied the autophagy protease ATG4B as a novel drug target in pancreatic cancer. We generated several knockout cell lines for the ATG4 family of proteins using CRISPR Genome editing and studied the molecular regulation of ATG4 proteins by post-translational mechanisms. We discovered a novel type of post-translational regulation, the ATG8-ylation of proteins, that is regulated by ATG4 proteases (Figure 1). We are now interested in further investigating ATG8-ylation and its relevance in cellular processes other than autophagy. Furthermore, we continue our efforts to identify selective and potent inhibitors of ATG4B for applications in lung and pancreatic cancer, as well as the development of CRISPR-based screening methods (Figure 2). 

Kooperationspartner / Collaborations

• Manju Kurian, University College London
• Stephanie Kermorgant, Queen Mary University London
• Vania Braga, Imperial College London
• Helene Plun-Favreau, University College London
• David Selwood, University College London
• AstraZeneca, UK/Sweden
• Benevolent AI, UK

Mitgliedschaften / Memberships

• Deutscher Hochschulverband
• NBIA Disorders Medical and Scientific Advisory Board
• University College London, Honorary Professor
• EU COST Action Proteocure 

Ausgewählte Publikationen / Selected Publications

A. Papandreou, C. Luft, S. Barral, J. Kriston-Vizi, M. Kurian, R. Ketteler. Automamted High-Content Imaging in iPSC-derived Neuronal Progenitor Cells. SLAS Discovery, (2023), accepted, doi:org/10.1016/j.slasd.2022.12.002

E. Tsefou, A.S. Walker, E.H. Clark, A.R. Hicks, C. Luft, K. Takeda, T. Watanabe, B. Ramazio, J.M. Staddon, T. Briston, R. Ketteler. Investigation of USP30 inhibition to enhance Parkin-mediated mitophagy: tools and approaches. BioRxiv, doi:org/10.1101/2021.02.02.429344. Biochem J, (2021), 478:4099-4118. doi: 10.1042/BCJ20210508. 

R. Ketteler, and Sharon Tooze. ATG4B – more than a protease? Trends in Cell Biology, (2021), 31:515-516. Doi:10.1016/j.tcb.2021.04.003. 

A. Agrotis, L. von Chamier, H. Oliver, T. Singh and R. Ketteler. Human ATG4 autophagy proteases reverse ubiquitin-like attachment of LC3/GABARAP to other cellular proteins.  J Biol Chem, (2019), 294:12610-21. 

N. Malod-Dognin, J. Petschnigg, S.F. Ludwien Windels, J. Povh, R. Ketteler, and N. Przulj. Tissue-specific integrated cells reveal cancer-specific and pan-cancer oncogenes. Nature Commun (2019), 10:805. 

D. Frampton, G. Marino, L. Butcher, G. Pollara, J. Kriston-Vizi, R. Austin, H. Schwenzer, K. Ferreira de Castro, B. Chain, R. Ketteler, M. Stratton, E. Murchison, R.A. Weiss, S. Beck, and A. Fassati. Molecular signatures of regression of the canine transmissible venereal tumor. Cancer Cell (2018), 33:620-633. 

M. Pathania, N. De Jay, N. Maestro, A. S. Harutyunyan, J. Nitarska, P. Pahlavan, S. Henderson, L. G. Mikael, A. Richard-Londt, Y. Zhang, J. R. Costa, S. Hebert, S. Khazaei, N. Samir Ibrahim, J. Herrero, A. Riccio, S. Albrecht, R. Ketteler, S. Brandner, C. L. Kleinman, N. Jabado, and P. Salomoni. H3.3^K27Mcooperates with p53 loss and PDGFRA gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas. Cancer Cell (2017), 32:685-700.

N. Pengo, A. Agrotis, K. Prak, and R. Ketteler. ULK1 Inhibits LC3 Processing by Phosphorylation and Inactivation of Autophagy Protease ATG4B. Nature Commun (2017), 8:294.

E. Shanks, R. Ketteler, and D. Ebner. Academic Drug Discovery within the United Kingdom: a Reassessment. Nature Rev Drug Discov (2015), 14:510. 

Z. Yao, J. Petschnigg, R. Ketteler, and I. Stagljar. Application Guide for OMICs Approaches to Cell Signaling. Nature Chem Biol (2015), 11:387-397.