1) Discovery of a novel post-phosphorylation signaling mechanism. Although phosphorylation on Ser/Thr-Pro motifs is a key signaling mechanism, little was known about the phosphorylation-induced conformational change or its consequences. Our laboratory has identified the phosphorylated Ser/Thr-Pro-specific prolyl isomerase Pin1 and demonstrated that Pin1 induces conformational changes in phosphoproteins. Such conformational changes regulate protein catalytic activity, dephosphorylation, protein interaction, subcellular location, and/or turnover.
2) Discovery of the phosphorylated Ser/Thr-binding module. Although phosphorylated Tyr-binding modules and phosphorylated Ser/Thr-binding proteins have been characterized, phosphorylated Ser/Thr-binding modules were not described. Our laboratory has demonstrated that a subset of WW domains function as specific phosphorylated Ser/Thr-Pro-binding modules that play an essential role in mediating the phosphorylation-dependent protein interaction.
3) Demonstration of novel roles for Pin1 in Alzheimer's disease and cancer. The neurofibrillary tangles composed of hyperphosphorylated tau are a hallmark of Alzheimer's disease. Our laboratory has found that Pin1 is the first molecule that can restore the function of phosphorylated tau directly or indirectly promoting its dephosphorylation. However, Pin1 is depleted in Alzheimer's disease brains, which may accelerates tau phosphorylation, tangle formation and neuronal death. In contrast, Pin1 is overexpressed in many human tumors, and activates the cyclin D1 promoter in cooperation with the Ras signaling pathway or the b-catenin pathway. Furthermore, Pin1 knockout mice have many phenotypes similar to those resulted from disrupting the cyclin D1 gene. Thus, overexpression of Pin1 may act as a tumor marker and promote tumor growth. In addition, we have identified a Pin1 inhibitor that has potent anti-cancer activity, suggesting that Pin1 may be a new anticancer target.
4) Demonstration of a novel role for the telomeric protein Pin2/TRF1 in the mitotic checkpoint. Telomeres are important for maintaining the genome stability and proliferation capacity, but their roles in cell cycle checkpoint were not clear. Our laboratory has identified Pin2 as a new isoform of the telomeric protein Pin2/TRF1 and shown it to be important for the G2/M checkpoint by functioning as an ATM substrate and for the spindle checkpoint by interacting with spindle microtubules. Thus, Pin2/TRF1 is critical for the telomere-mediated mitotic checkpoint regulation.
(5) Discovery of the novel and potent telomerase inhibitor PinX1. Telomerase is critical for cancer and aging, but its endogenous inhibitors have not been described. The results from our laboratory, which have been submitted for publication, have shown that PinX1, one of four new Pin2-interacting proteins that we recently cloned, is a potent telomerase inhibitor and forces tumor cells into crisis upon overexpression. Depletion of PinX1 increases telomerase activity and increases tumorigenicity in nude mice, consistent with its chromosome localization at 8p23, a region with frequent loss of heterozygosity in a number of human cancers. Thus PinX1 is a potent telomerase inhibitor and may be a putative tumor suppressor.