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 Finally, I will talk about our unpublished work identifying a role for Pin1 in bladder cancer, which implicates Pin1 in regulating cholesterol biosynthesis.
