Molecular Signaling Group
Head: Prof. Ivan Dikic
Research in the Dikic group is centered around the two major cellular quality control pathways: the ubiquitin system and autophagy. As such they provide protection against rapid aging and various human diseases and are involved in almost all cellular signaling processes.
Ubiquitin (Ub) is a highly conserved 76-amino acid polypeptide that is covalently attached to target proteins through a universally conserved three-step enzymatic process involving ubiquitin activating (E1), ubiquitin conjugating (E2) and ubiquitin ligating (E3) enzymes. Proteins can be modified by one (mono-ubiquitination) or several (multi-ubiquitination) single ubiquitin molecule(s). In addition, polyubiquitination of substrates occurs by the conjugation of ubiquitin proteins through one of its 7 lysine residues (K6, K11, K27, K29, K33, K48 and 63) or the N-terminal Methionine (M1) forming ubiquitin chains. Each type of Ub linkage is specifically recognised by specialised ubiquitin binding domains (UBD). To date, 20 families of UBDs have been characterized according to their specificity for Ub linkages (figure 1).
Given its high versatility, ubiquitination of proteins impacts almost all cellular pathways such as DNA repair, the immune response, endocytosis, autophagy, signaling and protein degradation (Hershko et al., 2000)
Figure 1: Ubiquitin binding domains recognise specific Ub linkages and have specialised functions. From Rajalingam and Dikic, 2016
Autophagy is a lysosome-mediated intracellular degradation pathway, which involves the formation of double-membrane vesicles (autophagosomes) that sequester portions of the cytoplasm or organelles and eventually fuse with the lysosome, where their cargo is degraded (figure 2). At first, autophagy was assumed to be a non-selective process to generate essential nutrients and building blocks required during cell starvation. However, during the last years, it became clear that autophagy is a tightly regulated, selective process that enables the specific degradation of damaged organelles, such as mitochondria (“mitophagy”), endoplasmic reticulum (“ER-phagy”) or invaded pathogens (“xenophagy”), maintaining cellular homeostasis.
Figure 2: Overview of selective autophagy. From (Stolz et al., 2014)
Prof. Ivan Dikic
Ivan was trained as a medical doctor in his hometown Zagreb (Croatia), before joining the lab of Joseph Schlessinger in New York in 1992 to pursue a PhD thesis in molecular biology. He moved back to Europe in 1997 to start his own group at the Ludwig Institute for Cancer Research in Uppsala (Sweden). In 2002, Ivan accepted a professorship at Goethe University and was appointed as director of the Institute of Biochemistry II in 2009. In parallel, he was the founding director of the Buchmann Institute for Molecular Life Sciences (BMLS), where he until today sustains an outstation lab. His research is dedicated to deciphering the molecular mechanisms of cellular signaling pathways, which have a high relevance to human diseases such as cancer, neurodegenerative disorders and inflammation. He was awarded with numerous recognitions, amongst them the Gottfried Wilhelm Leibniz Prize 2013 and election to the German National Academy of Sciences Leopoldina. Link to Director's page
Anshu joined Dikic group as a PhD student in Sept 2017 and is currently focusing on Quantitative profiling of lysosomal ubiquitylome in altered physiological scenarios. He obtained his Bachelor's degree (B.Sc) from Narendrapur Ramkrishna Mission Residential College and his Master's degree (M.Sc) from Jadavpur University. After having a brief exposure as CSIR-Junior Research Fellow in Indian Institute of Chemical Biology, Kolkata, he moved to Frankfurt.
Dr. Florian Bonn
Florian studied biochemistry at the University of Greifswald. After graduating in 2009 he started his PhD studies also in Greifswald at the Institute for Microbiology in the labs of Michael Hecker and Dörte Becher. During his dissertation he investigated the antibiotic stress response of Staphylococcus aureus with gel-free proteomics. In addition, he worked as an LC-MS specialist in the institute and could gather experience with a wide range of mass spectrometers. Florian completed his PhD work in 2015 and after a short PostDoc in Greifswald he joined Ivan Dikics group in April 2016. As part of the SFB 1177 Florian is responsible for mass-spectrometry and assisting the group in development of new protocols for proteomic experiments.
Dr. Adriana Covarrubias
Adriana was born in La Serena, Chile. She obtained her Agronomic sciences degree at the University of La Serena. Her thesis was focused on the tolerance strategies under abiotic stress in Chenopodium quinoa. Adriana then decided to study a PhD in Cellular and Molecular Biology at the University Austral of Chile, Valdivia (Chile). Adriana studied the Vitamin C homeostasis at the Central Nervous System and first focused on how ascorbic acid regulates the trafficking of SVCT2 transporter and second how the failure in the ascorbic acid homeostasis impaired the glucose uptake modulation in Huntington disease under the supervision of Dr. Maite A. Castro. In November 2018 Adriana joined the laboratory of Molecular Signaling of Prof. Dikic as a Postdoctoral researcher investigating the role of linear ubiquitination in the remodeling heart.
Yangxue was born and grew up in China. After high school Yangxue obtained her bachelor degree at the Bochum University, Germany and master degree with a focus on molecular biology at the Heidelberg University, Germany. She worked in MPI for Molecular Physiology in Dortmund, ZMBH and DKFZ in Heidelberg, and has good experience in protein purification and interaction investigation. She did her master thesis in the lab of Roberto Zoncu in the University of California, Berkeley, where She worked on of molecular mechanism for activation of the master growth regulator mTORC1. She became interested in molecular signaling, thus she joined the Dikic group as a PhD student in October 2018.
Javier Garcia Pardo
Javier was born in Manresa, Barcelona, Spain. After high school he obtained both a degree in Biology and a degree in Biochemistry at the Autonomous University of Barcelona. Following this, he completed his Master’s degree in Biochemistry at the same university.
During the PhD Javier was focused on the structural and functional characterization of novel regulatory and digestive metallocarboxypeptidases. Javier completed his PhD in Biochemistry, Molecular Biology and Biomedicine in 2015 in the group of Protein Engineering and Proteomics headed by Prof. F. X. Avilés at the Institute of Biochemistry and Biomedicine (IBB-UAB). The same year, he started a postdoctoral period at the same laboratory. Afterwards, he continued his career as a postdoctoral scientist in the group of Prof. Daniel Ruiz-Molina laboratory at the Catalan Institute of Nanoscience and Nanotechnology (ICN2), developing novel Nanostructured Coordination Polymers for biomedical applications. During all these years, he performed different short-term visits to other research groups, such as the laboratory of Prof. Lloyd D. Fricker (Albert Einstein College of Medicine, New York, USA) or the laboratory of Prof. Sir Tom Blundell (Dpt. of Biochemistry, University of Cambridge, Cambridge, UK). Javier’s most significant discovery is the structural characterization of Carboxypeptidase O, a novel human digestive carboxypeptidase with particular substrate specificity against acidic residues.
He joined the Dikic lab in September 2018 and he is currently working with reticulons, a group of evolutionary conserved proteins residing in the ER and involved in membrane curving. He is also trying to investigate the structure and mechanism of human DNA-dependent metalloproteases and in the discovery of new pharmacological targets for the NF-kB pathway.
Marcel studied biology at the University of Giessen, Germany, to obtain his master degree with a focus on immunology and genetics in 2015. He did his master thesis at the Institute of Immunology, Giessen, where he investigated the Interleukin-1 receptor signaling complex. After a research internship in the lab of Henning Walczak, Cancer Institute University College London, Marcel joined the lab of Ivan Dikic as a PhD student. During his PhD he is working on cytokine signaling pathways and inflammation response.
Antonia obtained her Bachelor’s degree in Biology at Goethe University in Frankfurt am Main. After graduating in 2015 she started studying Marine Biology at the University of Rostock and received her Master’s degree. In May 2018, Antonia joined Ivan Dikic’s group as a Technical Assistant to support the lab.
Dr. Lina Herhaus
After high school Lina obtained her first lab work experience in Mexico at the Research centre ECOSUR in San Cristóbal de las Casas. She then decided to study Applied Biology at Hochschule Bonn-Rhein-Sieg (Germany) and Molecular Biology at the University of Dundee (UK) where she obtained a double degree with Honours. Lina performed her PhD studies at the MRC Protein Phosphorylation and Ubiquitylation Unit in Dundee under the supervision of Gopal Sapkota. Her dissertation focused on how deubiquitylating enzymes regulate the TGF-beta and BMP signaling pathways. Lina is now an EMBO fellow in the lab of Ivan Dikic in Frankfurt (Germany), where she will investigate the role of ubiquitylation on tumor-stroma crosstalk.
Yaobin obtained his master degree in Pharmacology at Soochow University, China. Under the mentorship of Guoqiang Xu, he studied the mechanism by which Lenalidomide treats the blood cancer multiple myeloma. He joined the lab of Ivan Dikic as a PhD student in May 2016. During his PhD he is now working on the indentification of the activity and substrates of Legionella effector.
Dr. Timurs Maculins
Timurs was born in Riga, Latvia, where he studied medicine in Riga Stradiņš Medical University. He has joint academic research via a Master of Science degree at the Erasmus Medical Centre Rotterdam with the support of the Huygens Scholarship awarded by the Netherlands Organization for International Cooperation in Higher Education. Timurs pursued his interests in fundamental research by joining the laboratory of Karim Labib at the Manchester Cancer Research Centre in the United Kingdom after receiving a doctoral studentship from Cancer Research UK. Using the budding yeast as a model organism in his doctoral work, Timurs studied a role of a novel enzyme, known as SCFDia2 ubiquitin ligase, during DNA replication in the S phase of the cell cycle. Tim’s most significant discovery is an observation that cells lacking SCFDia2 accumulate ‘un-disassembled’ replication complexes at the end of S phase, which is rescued by re-expression of the ligase. This constitutes a key step of a fundamental mechanism, known as replisome disassembly, which Timurs and his colleagues co-discovered in eukaryotes.
Timurs continued his career as a postdoctoral scientist in the pharmaceutical industry in a collaborative project between the AstraZeneca High-Throughput Screening Centre and the academic laboratory headed by Ronald Hay. Following his interests in ubiquitin drug discovery, Timurs developed a novel approach for modulating the activity of mammalian ubiquitin ligases with chemical compounds. This field of drug discovery holds a great therapeutic potential, but in the absence of reliable screening technologies remains largely unexplored. Working in close collaboration with Hay’s laboratory, Timurs has developed a robust method for pharmacological inhibition of ubiquitin ligases in mammalian cells and utilized it to discover small molecule inhibitors against Rnf8 enzyme that regulates DNA damage response.
In late 2015 Timurs joined a collaborative project between the laboratory headed by Ivan Dikic and Fraunhofer IME for developing innovative approaches for pharmacological targeting of the ubiquitin system. Most recently, Timurs has received the Human Frontier Science Program postdoctoral fellowship, which he will utilize for studying the role played by ubiquitin ligase-like effectors during infection by lethal bacterial pathogens.
Dr. Hadir Marei
Hadir was born in Cairo, Egypt. She obtained her Bachelor’s degree in Biology with a minor in Chemistry at the American University in Cairo. During her Bachelor’s degree, she also participated in an Erasmus exchange program, where she conducted her third year at the University of St. Andrews, Scotland. Following her Bachelor’s, Hadir was awarded a Cancer Research UK studentship to conduct a four-year PhD program at the Cancer Research UK Manchester Institute (CRUKMI) in the Cell Signalling group headed by Angeliki Malliri. During her PhD, Hadir was focused on dissecting the molecular mechanisms involved in dictating the biological outcomes mediated by the small GTPase Rac1, a key regulator of cytoskeletal rearrangements and cell migration. Stemming from her interest in small GTPases, Hadir joined the Dikic group as a postdoctoral fellow, where she is currently investigating the role of regulators of Rab GTPases in modulating autophagy. Additionally, she is also exploring the interplay between cytoskeletal regulators and the trafficking machinery, under normal and pathological conditions. Given her scientific background, Hadir is also interested in identifying novel proteins that modulate the cytoskeleton, particularly following bacterial infection.
Dr. Mohit Misra
Mohit completed his master's degree in Biotechnology at JMI University, New Delhi in addition to a Postgraduate Diploma in Bioinformatics affiliated to NIELIT, Kolkata. He worked as a Junior Research Fellow at the International Center for Genetic Engineering and Biotechnology in the Recombinant Gene Products lab led by Dr. Navin Khanna. He moved to Germany to the Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg in the lab of Prof. Hermann Schindelin to obtain his PhD where he worked at the apex of the ubiquitylation pathway trying to decipher the structure-function relationship of the ubiquitin-activating enzyme (Uba1) and its interactions with the E2 enzymes. He also determined the structural basis of the variable potency of E1 inhibitors towards Uba1 which hold promise for cancer therapy. After a brief postdoc in Würzburg, Mohit continues to pursue his fascination for ubiquitin and has joined the Dikic lab to explore the novel chemistry of serine ubiquitylation both structurally and biochemically.
Rukmini worked as a PhD student in the lab of Dr Oishee Chakrabarti at the Saha Institute of Nuclear Physics, Kolkata. She submitted her PhD thesis on E3 ligases and their importance in mitochondrial homeostasis in December 2016. Following this, she worked in the lab of Dr Tony Hunter at the Salk Institute, California. She has joined the Dikic lab in October 2017 and is currently working on ADP-ribosylation of ubiquitin in mammalian cells.
Dr. Véronique Schaeffer
Véronique did her PhD in joint supervision between the University of Basel (Switzerland) and the University of Strasbourg (France) investigating the role of endogenous neurosteroids in the regulation of neurodegenerative processes. Afterwards, Véronique worked in the group of Michel Goedert (MRC - Laboratory of Molecular Biology, Cambridge, UK) where she has developed and characterized a transgenic mouse model of TDP-43 proteionopathy. She also conducted another project investigating the effect of autophagy stimulation on neurodegeneration in a mouse model of tauopathy. Véronique is now doing a second postdoc in the lab of Ivan Dikic where she intends to investigate further autophagic pathways.
Dr. Varun Shah
Varun completed his master’s degree in biotechnology from Utkal University, Bhubaneswar, India. He then joined Dr. Maddika Subba Reddy’s laboratory for PhD at Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India. His dissertation was focused on the identification and characterization of CRL7SMU1 , a multi-subunit E3 ligase in the regulation of genomic stability. He has joined Ivan Dikic's lab in November 2018 where he intends to investigate the roles of E3 ubiquitin ligases and deubiquitinases in lung cancer pathogenesis.
Dr. Donghyuk Shin
Donghyuk obtained his Master and PhD degrees in department of biological sciences, Sungkyunkwan University, South Korea. During his PhD research, he revealed the site-specific mono-ubiquitination of Rab5 and its physiological functions under the supervision of Prof. Sangho Lee. He also tried to understand structure of linear ubiquitin chains by combining X-ray crystallography and small angle X-ray scattering. After obtained his PhD in Aug. 2017, he moved to Frankfurt and joined the Dikic’s lab as a postdoc since Nov. 2017. He is currently trying to understand the structure and function of various proteins related to phosphoribose dependent ubiquitination.
Dr. Alexandra Stolz
Alexandra received her PhD under supervision of Dieter H. Wolf in the Institute of Biochemistry in Stuttgart, Germany, working on the identification and characterization of new players of endoplasmic reticulum associated protein degradation (ERAD). She started at IBCII in the Protein Engineering Group of Andreas Ernst in September 2013 focusing on the development of peptide-based ATG8 sensors. In 2015 she joined the lab of Ivan Dikic for functional validation of the beforehand engineered sensors in mitophagy and xenophagy. Alexandra is now working on the selective degradation of the endoplasmic reticulum (ER-phagy) with focus on the FAM134 family.
Head: Prof. Ivan Dikic
Institute of Biochemistry II
University Hospital Frankfurt
Theodor-Stern-Kai 7 / Building 75
60590 Frankfurt am Main
Lab 1 Tel: +49 (0) 69 6301 4862
Lab 2 Tel: +49 (0) 69 6301 83752