Prolyl isomerase Pin1 and neurotrophins: a loop that may determine the fate of cells in cancer and neurodegeneration

Abstract

Increased survival, differentiation, and apoptotic death are common mechanisms relevant for both cancer and neurodegenerative diseases. Although these disorders are characterized by different manifestations, it appears that a common mechanism may be present which directs the fate of a cell to either degeneration or proliferation. There are two classes of proteins that have been extensively investigated in these diseases but their possible interaction during signal transduction has not been studied. Prolyl isomerase Pin1 is an enzyme which translates Ser/Thr-Pro phosphorylation into conformational changes able to modify the activities of its substrates. Its role in cancer development has been linked to its capacity to induce conformational changes to the tumor suppressor gene p53. Neurotrophins belong to a family of proteins that induce opposite effects on neuronal cells such as increased survival, development, and function. According to their function, alteration of these proteins during neurodegenerative processes has been investigated and reported in a number of experimental paradigms involving animal models and humans. However, in recent years, it has been shown that Pin1 downregulation is present in neurodegenerative disorders, while increased expression of neurotrophins and their receptors is found in certain types of cancer and correlate with poor prognosis. Notably, at the level of signal transduction, Pin1 and neurotrophin activity regulate the outcome of similar pathways such as proline-directed kinase and, most importantly, p53 signaling. Thus the possible existence of a loop between Pin1 and neurotrophins was investigated to understand the pathogenesis of these diseases.