My laboratory has pioneered in elucidating the role of Pin1-catalyzed cis-trans conformational regulation after proline-directed phosphorylation in cell signaling in health and disease, and also identified novel Pin1-targeted therapies in cancer, autoimmune disorders, traumatic brain injury and Alzheimer’s disease.
Protein phosphorylation regulates diverse cellular processes in health and disease. Our lab has discovered a unique enzyme called Pin1 that introduces a pivotal new twist in phosphorylation signaling by converting phosphorylated proteins between two functionally distinct conformations, cis and trans. Deregulation of this novel signaling mechanism leads to accumulation of proteins in the pathogenic conformations, thereby having profound impact on the development of many diseases, especially those related to aging or stress such as Alzheimer’s disease, traumatic brain injury, cancer and autoimmune disorders. More significantly, our lab has recently developed innovative antibody technology that can specifically detect and eliminate these pathogenic conformations, such as cis tau protein, a major early driver of neurodegeneration, for early diagnosis and treatment of brain injury and Alzheimer’s disease. Our recent development of Pin1 high-throughput drug screens has identified a series of new Pin1 inhibitors, including all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as synergistic Pin1 inhibitors to block multiple cancer-driving pathways and eliminate cancer stem cells. Notably, the ATO+ATRA combination has revolutionized APL treatment from highly fatal to highly curable, with good safety profiles, but their drug targets remain elusive. Our results identify Pin1 as a major target for ATRA+ATO, and suggest that Pin1 inhibitors such as ATRA and ATO may be used to overcome drug resistance by blocking numerous cancer-driving pathways and eliminating cancer stem cells. These discoveries have suggested a promising new paradigm for the development of diagnostics and therapeutics that specifically target the pathogenic protein conformations in a wide range of diseases.
The current projects focus on translating our new discoveries into clinical products for improving human health, notably Pin1 inhibitors to stop multiple cancer-driving pathways and conformation-specific antibody for early diagnosis and treatment of Alzheimer’s disease and traumatic brain injury.