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Revealing the ubiquitin and ubiquitin-like modification landscape in health and disease

Objective

Post-translational modifications (PTMs) of proteins are a major tool that the cell uses to monitor events and initiate appropriate responses. While a protein is defined by its backbone of amino acid sequence, its function is often determined by PTMs, which specify stability, activity, or cellular localization. Among PTMs, ubiquitin and ubiquitin-like (Ubl) modifications were shown to regulate a variety of fundamental cellular processes such as cell division and differentiation. Aberrations in these pathways have been implicated in the pathogenesis of cancer. Over the past decade high-throughput genomic and transcriptional analyses have profoundly broadened our understanding of the processes underlying cancer development and progression. Yet, proteomic analyses and the PTM landscape in cancer, remained relatively unexplored.
Our goal is to decipher molecular mechanisms of Ubl regulation in cancer. We will utilize the PTM profiling technology that I developed and further develop it to allow for subsequent MS analysis. Together with cutting-edge genomic, imaging and proteomic technologies, we will analyze novel aspects of PTM regulation at the level of the enzymatic machinery, the substrates and the downstream cellular network. We will rely on ample in-vitro and in-vivo characterization of Ubl conjugation to:a. Elucidate the regulatory principles of substrate specificity and recognition. b. Understand signalling dynamics in the ubiquitin system. c. Reveal how aberrations in these pathways may lead to diseases such as cancer. Identifying both the Ubl modifying enzymes and the modified substrates will form the basis for deciphering the molecular pathways in which they operate in the cell and the principles of their dynamic regulation. Revealing the PTM regulatory code presents a unique opportunity for the development of novel therapeutics. More broadly, our approaches may provide a new paradigm for addressing other complex biological questions involving PTM regulation.

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Topic(s)

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ERC-STG - Starting Grant

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Call for proposal

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(opens in new window) ERC-2015-STG

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Host institution

WEIZMANN INSTITUTE OF SCIENCE
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 500 000,00
Address
HERZL STREET 234
7610001 Rehovot
Israel

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Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 500 000,00

Beneficiaries (1)

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