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The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease

Nature Reviews Molecular Cell Biology volume 8, pages 904–916 (2007)Cite this article

Key Points

  • PIN1 (protein interacting with NIMA (never in mitosis A)-1) was originally identified as a protein that physically interacts with NIMA mitotic kinase and functionally suppresses its ability to induce mitotic catastrophe. PIN1 is a member of the evolutionarily conserved peptidyl-prolyl isomerase family of proteins, which encompasses cyclophilins, FK506-binding proteins and parvulins.

  • Unlike all other known prolyl isomerases, PIN1 binds to and catalyses the conversion of specific Pro-directed Ser/Thr phosphorylation motifs between the two completely distinct cis and trans conformations. Such conformational changes after phosphorylation have a profound impact on many key regulators in diverse cellular processes, including regulation of cell growth, stress responses, the immune response, germ cell development, neuronal differentiation and survival.

  • PIN1-catalysed phosphorylation-dependent prolyl isomerization has emerged as a unique molecular timer that modulates its multiple targets at various steps of a given cellular process to synergistically control the amplitude and duration of a cellular response or process.

  • PIN1 is tightly regulated under physiological conditions by multiple mechanisms, which include transcriptional regulation and post-translational modifications such as phosphorylation, oxidative modifications and ubiquitylation. PIN1 deregulation has an important role in a growing number of pathological conditions.

  • PIN1 is prevalently overexpressed in human cancers and its overexpression levels correlate with poor clinical outcome. Furthermore, PIN1 promotes oncogenesis by regulating multiple oncogenic signalling pathways at various levels.

  • PIN1 expression is induced during neuron differentiation and acts on tau and amyloid precursor protein (APP) to restore the biological function of tau and to promote non-amyloidogenic APP processing. However, PIN1 activity is inhibited by multiple mechanisms in Alzheimer's disease neurons and its deregulation may provide a link between neurofibrillary tangles and senile plaques, the two neuropathological hallmarks in Alzheimer's disease.

  • The PIN1-catalysed regulatory mechanism might offer potential new diagnostics and/or therapeutics for some diseases, especially cancer, Alzheimer's disease and asthma.

Abstract

Protein phosphorylation regulates many cellular processes by causing changes in protein conformation. The prolyl isomerase PIN1 has been identified as a regulator of phosphorylation signalling that catalyses the conversion of specific phosphorylated motifs between the two completely distinct conformations in a subset of proteins. PIN1 regulates diverse cellular processes, including growth-signal responses, cell-cycle progression, cellular stress responses, neuronal function and immune responses. In line with the diverse physiological roles of PIN1, it has also been linked to several diseases that include cancer, Alzheimer's disease and asthma, and thus it might represent a novel therapeutic target.

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Figure 1: Structural basis for the unique specificity of PIN1 towards specific pSer/Thr-Pro motifs.
Figure 2: PIN1-catalysed prolyl isomerization regulates a spectrum of target activities.
Figure 3: PIN1 promotes oncogenesis by regulating multiple oncogenic signalling at various levels.
Figure 4: The regulation of tau function and APP processing by PIN1 in healthy and Alzheimer's neurons.

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Acknowledgements

We are grateful to L. Nicholson, L. Cantley, B. Neel and T. Hunter for advice, to Y. Liou and L. Nicholson for their contributions to Box 1 and Figures 1 and 2, and to the members of the Lu laboratory for stimulating discussions. Work done in the authors' laboratories is supported by National Institutes of Health grants to X. Z. Z. and K.P.L., and gift donations from EPIX Pharmaceuticals and Merck Research Laboratories Boston to K.P.L.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, NRB1030, Boston, 02215, Massachusetts, USA

    Kun Ping Lu & Xiao Zhen Zhou

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Supplementary information

Supplementary information S1 (table)

PIN1 substrates, targeting sites and functional consequences (PDF 220 kb)

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DATABASES

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Glossary

Pro-directed kinase

A protein kinase that phosphorylates certain Ser/Thr residues that precede a Pro residue (Ser/Thr-Pro motifs).

Peptidyl-prolyl cis/trans isomerase

A member of a large superfamily of enzymes that catalyse cis/trans isomerization of Pro imidic peptide bonds by reducing the energy barrier between these two states.

Polo-like kinase

A family of protein kinases that regulate spindle assembly, mitotic entry and chromosome segregation.

WW domain

A protein-interacting module that contains ∼38 amino acid residues folded into a three-stranded β-sheet structure. The domain name is derived from two conserved Trp residues that are spaced 20–22 residues apart within the consensus sequence.

Amyloid precursor protein

A transmembrane glycoprotein that is sequentially cleaved to generate Aβ peptides in Alzheimer's disease.

E2F

A family of transcription factors.

Mitotic catastrophe

A type of cell death that is linked to abnormal activation of the mitotic kinases due to deficient cell-cycle checkpoints.

Wee box

A small region in the N-terminal regulatory domain of Xenopus laevis somatic Wee1 that is required for both normal kinase activity and mitotic inactivation of the kinase.

Anaphase promoting complex

A multiprotein complex that is activated during mitosis to initiate anaphase and functions as an E3 ubiquitin ligase to ubiquitylate proteins for degradation by the 26S proteasome.

G2–M phase

A stage in the cell cycle whereby chromosomes that have been duplicated during S phase undergo compaction in preparation for mitosis.

Topoisomerase

A class of enzymes that alter the supercoiling of DNA. This allows the occurrence of DNA replication or transcription, or chromatin condensation.

Centrosome

A major microtubule-organizing structure in animal cells that determines the organization of the mitotic spindle poles that segregate duplicated chromosomes between dividing cells.

Ubiquitin E3 ligase

An enzyme that facilitates the attachment of ubiquitin onto substrates.

Tau

A microtubule-binding protein that promotes microtubule assembly.

Activator protein-1

(AP1). A transcription factor that consists of either a Jun–Jun homodimer or a Jun–Fos heterodimer.

Senile plaques

One of the two neuropathological hallmarks found in the brains of patients with Alzheimer's disease. Plaques are primarily composed of Aβ peptides that are derived from amyloid precursor protein.

Neurofibrillary tangles

The other neuropathological hallmark found in the brains of patients with Alzheimer's disease. Tangles consist mainly of the microtubule-binding protein tau in a hyperphosphorylated state.

TG3

A phospho- and conformation-specific monoclonal antibody that recognizes the phosphorylated Thr231 in the tangle-specific conformation of tau observed in brains from patients with Alzheimer's disease.

Aβ42

42-amino-acid-long Aβ peptides that are derived from amyloid precursor protein after sequential cleavages by β- and γ-secretases.

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Lu, K., Zhou, X. The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol 8, 904–916 (2007). https://doi.org/10.1038/nrm2261

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