Peptidyl-prolyl cis–trans isomerase Pin1 in ageing, cancer and Alzheimer disease

Abstract

Phosphorylation of proteins on serine or threonine residues preceding proline is a key signalling mechanism in diverse physiological and pathological processes. Pin1 (peptidyl-prolyl cis–trans isomerase) is the only enzyme known that can isomerise specific Ser/Thr-Pro peptide bonds after phosphorylation and regulate their conformational changes with high efficiency. These Pin1-catalysed conformational changes can have profound effects on phosphorylation signalling by regulating a spectrum of target activities. Interestingly, Pin1 deregulation is implicated in a number of diseases, notably ageing and age-related diseases, including cancer and Alzheimer disease. Pin1 is overexpressed in most human cancers; it activates numerous oncogenes or growth enhancers and also inactivates a large number of tumour suppressors or growth inhibitors. By contrast, ablation of Pin1 prevents cancer, but eventually leads to premature ageing and neurodegeneration. Consistent with its neuroprotective role, Pin1 has been shown to be inactivated in neurons of patients with Alzheimer disease. Therefore, Pin1-mediated phosphorylation-dependent prolyl isomerisation represents a unique signalling mechanism that has a pivotal role in the development of human diseases, and might offer an attractive new diagnostic and therapeutic target.