Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations

Nakatsu, Yusuke; Matsunaga, Yasuka; Yamamotoya, Takeshi; Ueda, Koji; Inoue, Yuki; Mori, Kyoichi; Sakoda, Hideyuki; Fujishiro, Midori; Ono, Hiraku; Kushiyama, Akifumi; Asano, Tomohiko

doi:10.3390/ijms17091495

Cited by 44 publications

(57 citation statements)

References 118 publications

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“…First, insulin signaling plays critical roles in lipogenesis, by inducing the expressions of two rate-limited enzymes, acetyl CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN) [38,39]. Pin1 reportedly enhances insulin signaling via its association with insulin receptor substrate 1 (IRS-1) and Akt [37,40].…”

Section: Role Of Pin1 In the Pathogenesis Of Hepatic Steatosismentioning

confidence: 99%

Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins

Inoue

Nakatsu

Yamamotoya

et al. 2019

Cells

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Pin1 is one of the three known prolyl-isomerase types and its hepatic expression level is markedly enhanced in the obese state. Pin1 plays critical roles in favoring the exacerbation of both lipid accumulation and fibrotic change accompanying inflammation. Indeed, Pin1-deficient mice are highly resistant to non-alcoholic steatohepatitis (NASH) development by either a high-fat diet or methionine–choline-deficient diet feeding. The processes of NASH development can basically be separated into lipid accumulation and subsequent fibrotic change with inflammation. In this review, we outline the molecular mechanisms by which increased Pin1 promotes both of these phases of NASH. The target proteins of Pin1 involved in lipid accumulation include insulin receptor substrate 1 (IRS-1), AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase 1 (ACC1), while the p60 of the NF-kB complex and transforming growth factor β (TGF-β) pathway appear to be involved in the fibrotic process accelerated by Pin1. Interestingly, Pin1 deficiency does not cause abnormalities in liver size, appearance or function. Therefore, we consider the inhibition of increased Pin1 to be a promising approach to treating NASH and preventing hepatic fibrosis.

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Section: Role Of Pin1 In the Pathogenesis Of Hepatic Steatosismentioning

confidence: 99%

Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins

Inoue

Nakatsu

Yamamotoya

et al. 2019

Cells

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“…We propose three models for how the phosphorylation of Ser 22 might regulate mDia: 1) phosphorylation may reduce the binding of RhoA and thus impair the activation of mDia, 2) phosphorylation may increase the affinity of the DID domain for the DAD domain, stabilizing the autoinhibitory conformation, or 3) phosphorylation may recruit liprin-␣ and mediate stress fiber dissolution. Interestingly, the prolyl isomerase Pin1 binds to pS/T -P motifs, where it catalyzes protein isomerization in a manner that can change protein binding partners (reviewed (83)(84)(85)). The F10 consensus motif identified in the SILAC screen contained a central pS/T -P motif (Fig.…”

Section: Molecular and Cellular Proteomics 16 Supplement 4 S137mentioning

confidence: 99%

Proteomic Screen for Cellular Targets of the Vaccinia Virus F10 Protein Kinase Reveals that Phosphorylation of mDia Regulates Stress Fiber Formation

Greseth

Carter

Terhune

et al. 2017

Molecular & Cellular Proteomics

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Vaccinia virus, a complex dsDNA virus, is unusual in replicating exclusively within the cytoplasm of infected cells. Although this prototypic poxvirus encodes >200 proteins utilized during infection, a significant role for host proteins and cellular architecture is increasingly evident. The viral B1 kinase and H1 phosphatase are known to target cellular proteins as well as viral substrates, but little is known about the cellular substrates of the F10 kinase. F10 is essential for virion morphogenesis, beginning with the poorly understood process of diversion of membranes from the ER for the purpose of virion membrane biogenesis. To better understand the function of F10, we generated a cell line that carries a single, inducible F10 transgene. Using uninduced and induced cells, we performed tablesotope abeling ofmino acids in ell culture (SILAC) coupled with phosphopeptide analysis to identify cellular targets of F10-mediated phosphorylation. We identified 27 proteins that showed statistically significant changes in phosphorylation upon the expression of the F10 kinase: 18 proteins showed an increase in phosphorylation whereas 9 proteins showed a decrease in phosphorylation. These proteins participate in several distinct cellular processes including cytoskeleton dynamics, membrane trafficking and cellular metabolism. One of the proteins with the greatest change in phosphorylation was mDia, a member of the formin family of cytoskeleton regulators; F10 induction led to increased phosphorylation on Ser Induction of F10 induced a statistically significant decrease in the percentage of cells with actin stress fibers; however, this change was abrogated when an mDia SerAla variant was expressed. Moreover, expression of a SerAsp variant leads to a reduction of stress fibers even in cells not expressing F10. In sum, we present the first unbiased screen for cellular targets of F10-mediated phosphorylation, and in so doing describe a heretofore unknown mechanism for regulating stress fiber formation through phosphorylation of mDia. Data are available via ProteomeXchange with identifier PXD005246.

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“…The detailed mechanism for Pin1-mediated PRDM16 degradation remains undetermined. Nevertheless, by regulating the activity of coactivators such as CRTC2 and PRDM16, Pin1 is involved in the regulatory mechanism governing the glucose metabolism and adipose thermogenesis (Nakatsu et al, 2016).…”

Section: Pin1 and The Transcription Co-regulatorsmentioning

confidence: 99%

Pinning Down the Transcription: A Role for Peptidyl-Prolyl cis-trans Isomerase Pin1 in Gene Expression

Chen

2020

Front. Cell Dev. Biol.

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Pin1 is a peptidyl-prolyl cis-trans isomerase that specifically binds to a phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif and catalyzes the cis-trans isomerization of proline imidic peptide bond, resulting in conformational change of its substrates. Pin1 regulates many biological processes and is also involved in the development of human diseases, like cancer and neurological diseases. Many Pin1 substrates are transcription factors and transcription regulators, including RNA polymerase II (RNAPII) and factors associated with transcription initiation, elongation, termination and post-transcription mRNA decay. By changing the stability, subcellular localization, protein-protein or protein-DNA/RNA interactions of these transcription related proteins, Pin1 modulates the transcription of many genes related to cell proliferation, differentiation, apoptosis and immune response. Here, we will discuss how Pin regulates the properties of these transcription relevant factors for effective gene expression and how Pin1-mediated transcription contributes to the diverse pathophysiological functions of Pin1.

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Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations

Cited by 44 publications

References 118 publications

Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins

Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins

Proteomic Screen for Cellular Targets of the Vaccinia Virus F10 Protein Kinase Reveals that Phosphorylation of mDia Regulates Stress Fiber Formation

Pinning Down the Transcription: A Role for Peptidyl-Prolyl cis-trans Isomerase Pin1 in Gene Expression

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