Hugues de Thé

Collège de France

Oncologie cellulaire et moléculaire

Année 2023-2024

Exploring the World of Protein Post-translational Modifications

Conférence - Tony Hunter : Post-translational Modifications of Proteins – Why Nature Chose Phosphate to Modify Proteins

Tony Hunter

Salk Institute, La Jolla, California, USA

Résumé

This lecture will provide an introduction to the world of post-translational modifications (PTMs) of proteins. Chemical modifications of protein surfaces serves as a mechanism to increase proteome diversity. More than 400 different PTMs are known, and PTM linkages can be either reversible or irreversible in nature. PTMs serve many functions, but reversible PTMs play particularly important roles in signal transduction, protein-protein interactions, subcellular localization of proteins and protein degradation. All reversible PTMs, such as phosphorylation, utilize a writer enzyme that adds the PTM and an eraser enzyme that removes the PTM, and in many cases the modified protein is recognized by a reader protein that binds to the PTM itself in a local sequence-dependent manner, serving as a mechanism to read out the PTM signal.

I will review the major types of PTMs and their functions, focusing on protein phosphorylation, which is the most prominent PTM in eukaryotic cells. I will discuss the 150-year history of protein phosphorylation and why phosphorylation was selected as a PTM during evolution, the serendipitous discovery of tyrosine phosphorylation in 1979, and the development of selective tyrosine kinase inhibitors (TKIs) that target aberrant tyrosine phosphorylation. Currently, over 80 TKIs have been approved for use in cancer therapy and treatment of inflammatory conditions.

In the second half of the lecture, I will talk about the discovery of the Pin1 prolyl isomerase, the characterization of Pin1 as a pSer/Thr.Pro motif reader and its activity as a cis-trans prolyl isomerase. By isomerizing pSer/Thr.Pro sites, Pin1 regulates multiple signaling pathways and processes that utilize proline-directed protein kinases, like the CDKs and MAP kinases, including cell cycle progression and mitotic signaling. Cancer-associated proteins, such p53 and Myc, are important targets for Pin1, and I will discuss the reported role of Pin1 in breast cancer and pancreatic cancer, and efforts to generate Pin1-selective small molecule inhibitors for use in cancer therapy. Finally, I will talk about our unpublished work identifying a role for Pin1 in bladder cancer, which implicates Pin1 in regulating cholesterol biosynthesis.

Tony Hunter

Tony Hunter received his BA and PhD from the University of Cambridge, and did postdoctoral studies there and at the Salk Institute. Since 1975, he has been on the faculty of the Salk Institute, where he is the Renato Dulbecco Chair. In 1979, through his work on tumor viruses, he discovered a new class of protein kinases that phosphorylate tyrosine in proteins, establishing that dysregulated tyrosine phosphorylation by an activated tyrosine kinase can cause cancer. Tyrosine phosphorylation is a reversible protein modification essential for the regulation of a wide variety of cellular processes in multicellular eukaryotes, including transmembrane signal transduction by surface receptors. Hunter's work led to the realization that aberrant tyrosine phosphorylation is causal in several types of human cancer, and this has led to the successful development of small molecule inhibitors that target disease-causing tyrosine kinases, known as TKIs, such as GleevecTM.

Hunter has received many awards for his work on tyrosine phosphorylation, including the Sjöberg Prize for Cancer Research, and the Tang Prize for Biopharmaceutical Science, and is a Fellow of the Royal Society of London and a Member of the US National Academy of Sciences.

In recent work, he has been studying histidine phosphorylation of proteins, generating monoclonal antibodies specific for the two isoforms of phosphohistidine, which he is using to identify new histidine phosphorylated proteins, and to uncover a possible role for histidine phosphorylation in cancer. He is also investigating the role of stromal cells in pancreatic cancer, discovering that the leukemia inhibitory factor (LIF) cytokine secreted by cancer-associated fibroblasts is important for tumor progression.