Cancer and dementia are among the most common age-related diseases. Proline-directed serine/threonine phosphorylation is a central regulatory signaling mechanism in response to mitogens and stresses by altering protein conformation. However, whether these conformations are further regulated was unknown until our discovery of Pin1, a unique and conserved enzyme that can catalyze proline cis-trans conformational changes after phosphorylation. Our lab is the first one to show that Pin1 is tightly regulated normally and its aberration can lead to disease. Notably, too much Pin1 contributes to cancer, whereas too little Pin1 contributes to Alzheimer’s diseases. Our first high throughput Pin1 drug screen has led to the unexpected discoveries that Pin1 inhibition is to how deadly APL leukemia is cured and also renders pancreatic cancer eradicable, for the first time, with clinical trials being planned. Our development of a new generation of stereo-specific antibodies able to detect and remove cis or trans Pin1 substrate conformations has discovered cis P-tau as an early driver, therapeutic target, and biomarker of dementia in Alzheimer’s disease and after brain injury or stroke, with ongoing clinical trials. Our studies on Pin1 signaling thus uncover a unique signaling mechanism and offer a new paradigm to target only the abnormal protein conformations for early diagnosis and treatment of major age-related diseases.
Dr. Lu Laboratory and Dr. Zhou Laboratory, Western University, 1400 Western Road, SDRI Room 107, London, Ontario N6G 2V4, Canada. The co-crystal structures of Pin1 and its inhibitors are generated by Shaunik Sharma using Pymol.
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