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Identification of novel substrates for ubiquitin ligases involved in cell cycle and cell migration

Periodic Reporting for period 1 - LIGER (Identification of novel substrates for ubiquitin ligases involved in cell cycle and cell migration)

Reporting period: 2017-03-01 to 2019-02-28

Protein degradation via the proteasome-ubiquitin system (UPS) plays a crucial role in cellular homeostasis. Defects in this system are often associated with pathologic states like cancer or developmental abnormalities. E3-ubiquitin ligases are responsible for substrate recognition and subsequent degradation. Despite this fact, many of the ubiquitin ligases have not been paired with any specific substrate yet. In my project supported by MSCA, I focused on “orphan” ubiquitin ligases with unknown functions and substrates. The objectives of the project were based on systematic and functional analysis of these ubiquitin ligases. I aspire to select several of them potentially involved in processes underlying above mentioned pathological states. The main motto and relevance of this approach were centered on the idea that novel biological therapies in the future will require a deep understanding of cellular mechanisms required for cellular growth and survival and that only basic research and detailed biochemical analysis could provide these facts.
I selected several ubiquitin ligases involved in cellular growth and survival and affinity-purified their complexes. Systematic analysis and biochemical approaches led to the discovery of new substrates of these ligases and description of signaling pathways involved in these regulations. These results led us to conclusions and hypotheses describing the physiologic roles of these proteins. To confirm the physiological role of these ligases we prepared cellular and mouse models of their deficiencies and characterize their role in the complex context of cell or organism. Results obtained from the LIGER project were already presented in the CSHL - prestigious conference focused on the proteasome-ubiquitin system, where they were selected for oral and poster presentations. Besides the scientific community, this project has been presented to professionals active in scientific communication and museum exhibitions at ECSITE (15-17 June 2017, Porto) and at the 100.000th MSCA Fellow Awards Ceremony (27 September 2017, Brussels) with the attendance of Tibor Navracsics, Commissioner for Education, Culture, Youth and Sport.
Our research is focused on a basic understanding of the regulation of protein dynamics and degradation in the context of cell growth and cell survival. Dysregulation of protein degradation is common in an array of human diseases. Recently, it was shown that this dysregulation could be a relevant therapeutic target especially in the context of cancer and other cellular malformations (e.g. auto-immune syndromes). Our results show in great detail how certain ubiquitin ligases recognize their substrates and how are these interactions regulated by external stimuli such as stress. More, we developed mice models enlightening the roles of these ubiquitin ligases in a physiological context. We believe that our results could provide a scientific community necessary building blocks which, in the future, could help to develop new therapeutic strategies and thus be of importance for the society.
LIGAR project