Tony Hunter is invited by the Collège de France assembly, at the suggestion of Professor Hugues de Thé.
Reversible posttranslational modifications (PTM) of proteins, such as phosphorylation, regulate protein function and serve as a mechanism to increase the complexity and functionality of the proteome. Protein phosphorylation is involved in nearly all cellular processes, and a single cell can have 1000's of distinct phosphorylation events, driven by more than 500 protein kinases, including 90 tyrosine kinases (TKs), which play key roles in signaling pathways activated by soluble protein signals received from other cells. Constitutive signaling by active mutant TKs in cancer cells is a major driver mechanism, and this prompted development of a plethora of small molecule inhibitors as a novel class of cancer therapeutics; currently, 86 tyrosine kinase inhibitors (TKIs) are approved for clinical use. In my lectures, I will review the major types of PTMs and their functions, focusing on protein phosphorylation, which is the most prominent PTM in eukaryotic cells, and ubiquitylation/sumoylation. I will discuss the discovery of tyrosine phosphorylation and how this gave us new insights into intracellular signal transduction. In addition to serine, threonine and tyrosine, six other amino acids can be phosphorylated in proteins, including histidine, and I will describe our recent progress in unraveling the role of histidine phosphorylation as a regulatory process. I will also present our work on ubiquitylation and sumoylation and crosstalk between these PTMs and phosphorylation. Finally, I will discuss our efforts to target secreted factors involved in intercellular crosstalk between different cell types in pancreatic tumors as a new therapeutic approach to this devastating disease.
All lectures are in English.
