Pinning Down Signaling in the Immune System: The Role of the Peptidyl-Prolyl Isomerase Pin1 in Immune Cell Function

Waisman Center for Developmental Disabilities, Department of Pathology and Laboratory Medicine and UW-Madison School of Medicine and Public Health, Madison, WI 53705, USA.
Critical Reviews in Immunology (Impact Factor: 3.7). 02/2008; 28(1):45-60. DOI: 10.1615/CritRevImmunol.v28.i1.30
Source: PubMed


The peptidyl prolyl isomerase (PPIase) Pin1 has been recently implicated in cell cycle control and neuropathologies. There is now growing evidence that Pin1 plays an important role in the immune system and does so differentially from the related PPIases, cyclophilinA and FKBP. This review describes how Pin1 modulates cytokine expression by activated T cells and eosinophils and participates in T-cell and eosinophil apoptotic decisions both in vitro and in vivo. We highlight several possible immunologic diseases, including asthma, as well as organ transplant rejection, where anti-Pin1 therapeutics maybe of value.

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Available from: Stephane Esnault, Sep 11, 2014
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    • "Consistent with its wide-ranging effects on cellular metabolism, Pin1 is an important therapeutic target [10], [11], [12] in Alzheimer's disease [13], breast [14], [15], liver [16], prostate [17], [18], [19], lung [20], and colon cancers [2] as well as asthma [12], [21]. Drug companies such as Pfizer Global R&D [22], [23] and Vernalis Ltd [24], [25] as well as several academic laboratories [26], [27], [28], [29], [30] have targeted Pin1 for anti-cancer therapy. "
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    ABSTRACT: The peptidyl-prolyl isomerase Pin1 is over-expressed in several cancer tissues is a potential prognostic marker in prostate cancer, and Pin1 ablation can suppress tumorigenesis in breast and prostate cancers. Pin1 can co-operate with activated ErbB2 or Ras to enhance tumorigenesis. It does so by regulating the activity of proteins that are essential for gene expression and cell proliferation. Several targets of Pin1 such as c-Myc, the Androgen Receptor, Estrogen Receptor-alpha, Cyclin D1, Cyclin E, p53, RAF kinase and NCOA3 are deregulated in cancer. At the posttranscriptional level, emerging evidence indicates that Pin1 also regulates mRNA decay of histone mRNAs, GM-CSF, Pth, and TGFβ mRNAs by interacting with the histone mRNA specific protein SLBP, and the ARE-binding proteins AUF1 and KSRP, respectively. To understand how Pin1 may affect mRNA abundance on a genome-wide scale in mammalian cells, we used RNAi along with DNA microarrays to identify genes whose abundance is significantly altered in response to a Pin1 knockdown. Functional scoring of differentially expressed genes showed that Pin1 gene targets control cell adhesion, leukocyte migration, the phosphatidylinositol signaling system and DNA replication. Several mRNAs whose abundance was significantly altered by Pin1 knockdown contained AU-rich element (ARE) sequences in their 3' untranslated regions. We identified HuR and AUF1 as Pin1 interacting ARE-binding proteins in vivo. Pin1 was also found to stabilize all core histone mRNAs in this study, thereby validating our results from a previously published study. Statistical analysis suggests that Pin1 may target the decay of essential mRNAs that are inherently unstable and have short to medium half-lives. Thus, this study shows that an important biological role of Pin1 is to regulate mRNA abundance and stability by interacting with specific RNA-binding proteins that may play a role in cancer progression.
    PLoS ONE 01/2014; 9(1):e85427. DOI:10.1371/journal.pone.0085427 · 3.23 Impact Factor
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    • "More recent studies demonstrated that Pin1 modifies the conformation of a large number of kinases, phosphatases, and other signaling molecules in a wide range of cell types (see Table I), and suggested a role for Pin1 in the regulation of immune responses, independent of the activity of the related PPIases, cyclophilin A and FKBP. Thus, Pin1 was found to regulate cytokine production by activated T cells and eosinophils, participate in T-cell and eosinophil apoptotic decisions and play an essential role in the onset of immune-mediated diseases and anti-allograft immune responses [45]. Among the many proteins that are regulated by Pin1, the nuclear factor of activated T-cells (NFAT), a transcription factor that is critical for T lymphocyte activation and proliferation [55], is a prominent Pin1 binding target. "
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    ABSTRACT: Pin1 is a peptidyl-prolyl isomerase (PPIase) that catalyzes the conversion of specific Pro-directed Ser/Thr phosphorylation motifs between the cis and trans conformations. It has been implicated in multiple aspects of cell cycle regulation and neural differentiation. In addition, Pin1 is involved in cellular processes related to a number of human pathologies, including cancer and Alzheimer's disease. More recent studies provided evidence for the participation of Pin1 in the regulation of immune cell functions and immune responses, independent of the activity of the related PPIases, cyclophilin A and FKBP, also known as immunophilins. In this review we focus on the role of Pin1 in the regulation of innate and adaptive immune system cell functions. Pin1 mediated isomerization of phosphoproteins represents a unique signaling mechanism that regulates normal immune functions and contributes to the development of immunopathologies. It can therefore serve as a useful diagnostic tool and a potential therapeutic target.
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    • "Due to this phospho-specificity, Pin1 has been proposed to be a regulatory timer of various cell signaling processes and is involved in many important cellular functions including growth and proliferation , immune responses, transcription, and apoptosis (Lu et al., 2007; Yeh and Means, 2007; Esnault et al., 2008; Takahashi et al., 2008). Pin1 is also implicated in diseases such as cancer and Alzheimer's disease and is a potential therapeutic target (Lu et al., 2006; Yeh and Means, 2007; Takahashi et al., 2008). "
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    ABSTRACT: Pin1 is a phosphorylation-dependent peptidyl-prolyl isomerase (PPIase) that has the potential to add an additional level of regulation within protein kinase mediated signaling pathways. Furthermore, there is a mounting body of evidence implicating Pin1 in the emergence of pathological phenotypes in neurodegeneration and cancer through the isomerization of a wide variety of substrates at peptidyl-prolyl bonds where the residue preceding proline is a phosphorylated serine or threonine residue (i.e., pS/T-P motifs). A key step in this regulatory process is the interaction of Pin-1 with its substrates. This is a complex process since Pin1 is composed of two domains, the catalytic PPIase domain, and a type IV WW domain, both of which recognize pS/T-P motifs. The observation that the WW domain exhibits considerably higher binding affinity for pS/T-P motifs has led to predictions that the two domains may have distinct roles in mediating the actions of Pin1 on its substrates. To evaluate the participation of its individual domains in target binding, we performed GST pulldowns to monitor interactions between various forms of Pin1 and mitotic phospho-proteins that revealed two classes of Pin-1 interacting proteins, differing in their requirement for residues within the PPIase domain. From these observations, we consider models for Pin1-substrate interactions and the potential functions of the different classes of Pin1 interacting proteins. We also compare sequences that are recognized by Pin1 within its individual interaction partners to investigate the underlying basis for its different types of interactions.
    Frontiers in Physiology 02/2013; 4:18. DOI:10.3389/fphys.2013.00018 · 3.53 Impact Factor
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