Research Topic

Phosphorylation-Dependent Peptidyl-Prolyl Cis/Trans Isomerase PIN1

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Phosphorylation of proteins by proline-directed kinases, such as the cyclin-dependent kinases and mitogen-activated protein, at Ser/Thr-Pro sites are crucial for growth and development. The Ser/Thr-Pro bond can be isomerized by peptidyl-prolyl cis/trans isomerases, of which PIN1 is unique in its specificity ...

Phosphorylation of proteins by proline-directed kinases, such as the cyclin-dependent kinases and mitogen-activated protein, at Ser/Thr-Pro sites are crucial for growth and development. The Ser/Thr-Pro bond can be isomerized by peptidyl-prolyl cis/trans isomerases, of which PIN1 is unique in its specificity to phosphorylated Ser/Thr-Pro motifs.

Discovered in 1996 for its roles in cell cycle regulation, Pin1 knockout mice displayed phenotypes akin to CyclinD1-null mice. Consistent with its profound involvement in cell cycling, aberrant PIN1 activation is associated with many oncogenic pathways. As such, PIN1 has attracted intense interest due to its therapeutic potential, culminating in the recent development of PIN1 inhibitors as the foundation of decades of biochemical and structural studies. Of note, structure-based virtual screening has resulted in the development of covalent inhibitors, in particular KPT-6566, which bind covalently to the catalytic site of PIN1. Importantly, this interaction releases a quinone-mimicking drug, which acts with high specificity against cancer cells and has shown impressive efficacy in halting lung metastasis in vivo.

In addition, PIN1’s roles in conformationally modulating pThr668-Pro of Amyloid Precursor Protein and pThr231-Pro of Tau provide an entry point for treating neurodegenerative diseases. This has led to the recent development of monoclonal cis- and trans-specific pT231-Tau antibodies, with only cis-specific antibodies attenuating Tau-related pathology development in mouse models.

Remarkably, PIN1’s physiological role continues to expand. PIN1 is important for fibroblast growth factor receptor signaling in cranial suture closure via modulation of the conformation of phosphorylated RUNX2 and can serve as a therapeutic target for craniosynostosis. Work pioneered by the Lu group and others also revealed a key role for PIN1-IRAK signaling during allergic airway inflammation and tumor radio-resistance, the therapeutic potentials of which are currently being evaluated.

We can only summarize recent progresses in PIN1 research in light of the wealth molecular insights generated by past researches. We aim to capture a glimpse of the future in view of ongoing research.


Keywords: Phosphorylation, Isomerase, PIN1, Oncogenic Pathway


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