Pin1-Dependent Prolyl Isomerization Regulates Dephosphorylation of Cdc25C and Tau Proteins

Zhou, Xiao Zhen; Kops, Oliver; Werner, A.; Lu, Pei Jung; Shen, Minhui; Stoller, Gerlind; Küllertz, Gerhard; Stark, Michael J. R.; Fischer, Gunter; Lu, Kun Ping

doi:10.1016/s1097-2765(05)00083-3

Cited by 487 publications

(191 citation statements)

References 45 publications

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“…The prolyl isomerization by the catalytic domain of PIN1 of specific pThr/pSer-Pro motifs is described as facilitating this dephosphorylation. Dephosphorylation by PP2A of mutated Tau Thr231Ala phosphorylated by cdc2 is not stimulated by PIN1 what suggested that pThr231-Pro232 is thus a regulatory site [70]. Recent data also show that dephosphorylation by PP2A of pThr231-Tau is PIN1-dependent during neuronal differentiation and oxidative stress (unpublished data from Buée et al, [74,75]) 2.…”

Section: Stimulation Of Substrate Dephosphorylation By Pp2amentioning

confidence: 97%

“…PIN1 facilitates dephosphorylation by PP2A of both CDC25 and Tau [70]. The prolyl isomerization by the catalytic domain of PIN1 of specific pThr/pSer-Pro motifs is described as facilitating this dephosphorylation.…”

Section: Stimulation Of Substrate Dephosphorylation By Pp2amentioning

confidence: 99%

“…PIN1 can stimulate trans specific proline-directed kinases [73] and phosphatases, a few examples of the stimulation of the dephosphorylation by trans-specific prolinedirected PP2A phosphatase are here discussed [70].…”

Section: Stimulation Of Substrate Dephosphorylation By Pp2amentioning

confidence: 99%

“…However the catalytic domain alone, under certain condition of overexpression, seems to be able to sustain the essential function of PIN1 in yeast [70]. The PIN1At single domain homolog is a good model to try to understand the intriguing functional cooperation of PIN1 domains.…”

Section: The Pin1 Protein : Cooperation Between Both Domainsmentioning

confidence: 99%

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Exploring the Molecular Function of PIN1 by Nuclear Magnetic Resonance

Landrieu¹,

Smet²,

Wieruszeski³

et al. 2006

CPPS

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PIN1 participates in the regulation of a number of signalling pathways in the cell involving protein phosphorylation/dephosphorylation. Its role seems to be an essential control level in addition to the protein phosphorylation by proline-directed kinases. Its cellular function includes regulation of the cell cycle by interaction with phosphorylated mitotic proteins such as Cdc25 and transcription factors such as p53. PIN1 was shown to be involved in the malignant transformation of cells in breast cancer, by up regulation of cyclinD1 and is thought to be involved in the development of the AD by regulating the function of phosphorylated Tau. We propose here to discuss the molecular function of PIN1 at the atomic level based on data from the recent literature and our own results obtained by the technique of Nuclear Magnetic Resonance. PIN1 specifically interacts with pThr/pSer-Pro motifs and is constituted by two domains: a WW N-terminal domain that binds pThr/pSer-Pro epitopes and a prolyl cis/trans isomerase C-terminal catalytic domain. An exception to this organisation is found in the plant PIN1 homologous enzymes, like PIN1At from Arabidopsis thaliana, that are constituted of the sole catalytic domain. The molecular function of PIN1, binding to and isomerization of pThr/pSer-Pro bonds, are thought to lead to several functional consequences. In a first mode of action, exemplified by its competition with the CKS protein, the interaction with PIN1 prevents interaction with other regulatory proteins, like ubiquitin-ligases that lead to degradation pathways. In a second mode of action, the idea is largely accepted that the local isomerization modifies the global conformation of the protein substrate and hence its intrinsic activity, although this has never been directly demonstrated. Finally, isomerization catalysis is thought to regulate the (de)phosphorylation of specific pThr/pSer-Pro motifs, exemplified by the stimulation of the dephosphorylation of pThr231 of Tau by the PP2A phosphatase.

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Section: Stimulation Of Substrate Dephosphorylation By Pp2amentioning

confidence: 97%

Section: Stimulation Of Substrate Dephosphorylation By Pp2amentioning

confidence: 99%

Section: Stimulation Of Substrate Dephosphorylation By Pp2amentioning

confidence: 99%

Section: The Pin1 Protein : Cooperation Between Both Domainsmentioning

confidence: 99%

See 2 more Smart Citations

Exploring the Molecular Function of PIN1 by Nuclear Magnetic Resonance

Landrieu¹,

Smet²,

Wieruszeski³

et al. 2006

CPPS

View full text Add to dashboard Cite

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“…We further evaluated the endogenous protein levels of TR3 in 293T cells and found that the expression levels of TR3 were elevated with increased amount of Pin1 transfection (Figure 2a,left), while declined by transfection of Pin1-siRNA (Figure 2a,right). Importantly, this effect of Pin1 on TR3 relied on its isomerase activity, as a Pin1 isomerasedead mutant K63A (Lu et al, 1999;Zhou et al, 2000) lost its ability to enhance TR3 expression (Figure 2a, left). Similar phenomena was also observed in HeLa cells (Supplementary Figure S2B).…”

Section: Pin1 Stabilizes Tr3 Protein By Blocking Its Degradationmentioning

confidence: 99%

Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

Wang

et al. 2011

Oncogene

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Pin1 regulates a subset of phosphoproteins by isomerizing phospho-Ser/Thr-Pro motifs via a 'post-phosphorylation' mechanism. Here, we characterize TR3 as a novel Pin1 substrate, and the mitogenic function of TR3 depends on Pin1-induced isomerization. There are at least three phospho-Ser-Pro motifs on TR3 that bind to Pin1. The Ser95-Pro motif of TR3 is the key site through which Pin1 enhances TR3 stability by retarding its degradation. Pin1 can also catalyze TR3 through phospho-Ser431-Pro motif, which is phosphorylated by extracellular signalregulated kinase 2 (ERK2), resulting in enhanced TR3 transactivation. Furthermore, Pin1 not only facilitates TR3 targeting to the promoter of cyclin D2, a novel downstream target of TR3, but also promotes TR3 to recruit p300, thereby inducing cell proliferation. Importantly, we found that Pin1 is indispensable for TR3 to promote tumor growth both in vitro and in vivo. Our study thus suggests that Pin1 has an important role in cell proliferation by isomerizing TR3.

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Potential of the Antibody Against cis–Phosphorylated Tau in the Early Diagnosis, Treatment, and Prevention of Alzheimer Disease and Brain Injury

Kondo

Albayram

et al. 2016

JAMA Neurol

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A lzheimer disease (AD) is the most common form of dementia in older individuals, currently affecting more than 5.4 million persons in the United States and 46.8 million people worldwide. 1 As the Baby Boomer generation ages and life expectancy continues to grow, these numbers are expected to increase dramatically; some estimates project that by 2050, AD will affect more than 130 million people worldwide at a cost of more than $1 trillion in the United States alone. 1 However, there are no effective treatments for AD. Because AD may take more than a decade to develop, understanding the early disease mechanisms is critical so that therapies can be developed to stop these early pathogenic events.Association of repetitive mild traumatic brain injury (rmTBI), as seen in contact sports, and even single moderate or severe TBI (ssTBI), as seen in military blasts, with the TBI-related neurodegenerative disorder termed chronic traumatic encephalopathy (CTE) is well known. 2-7 Traumatic brain injury is a leading cause of death or disability among children and young adults (aged 1-44 years). 8 Each year in the United States, more than 2.4 million emergency depart-ment visits, hospitalizations, or deaths are related to TBI, 9 and emergency department visits have increased 8-fold from 2006 to 2010. 10 Traumatic brain injury also affects approximately 20% of the 2.3 million soldiers deployed to Iraq and Afghanistan. 11 One in 3 US National Football League players also experiences neurocognitive problems in his lifetime. Moreover, epidemiologic studies suggest that patients with TBI may have a higher risk for dementia, even when compared with patients with non-TBI trauma. [12][13][14][15][16][17] However, the pathogenic mechanisms leading from acute TBI to chronic neurodegeneration are virtually unknown, 5-7 and whether TBI could cause AD has not been established. [18][19][20] Moreover, no effective treatments are available to mitigate secondary injury after TBI and/or to circumvent the development of neurodegeneration, such as CTE later in life. Because development of AD and CTE may take years to more than a decade, diagnoses and therapies that target early pathogenic events are sorely needed.Investigators 21-29 have identified a unique prolyl isomerase, Pin1, that prevents the development of tau-mediated neurodegeneration in AD by converting the phosphorylated Thr231-Pro motif in tau Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) share a common neuropathologic signature-neurofibrillary tangles made of phosphorylated tau-but do not have the same pathogenesis or symptoms. Although whether traumatic brain injury (TBI) could cause AD has not been established, CTE is shown to be associated with TBI. Until recently, whether and how TBI leads to tau-mediated neurodegeneration was unknown. The unique prolyl isomerase Pin1 protects against the development of tau-mediated neurodegeneration in AD by converting the phosphorylated Thr231-Pro motif in tau (ptau) from the pathogenic cis conformation to the physiologic tra...

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Pin1-Dependent Prolyl Isomerization Regulates Dephosphorylation of Cdc25C and Tau Proteins

Cited by 487 publications

References 45 publications

Exploring the Molecular Function of PIN1 by Nuclear Magnetic Resonance

Exploring the Molecular Function of PIN1 by Nuclear Magnetic Resonance

Prolyl isomerase Pin1 stabilizes and activates orphan nuclear receptor TR3 to promote mitogenesis

Potential of the Antibody Against cis–Phosphorylated Tau in the Early Diagnosis, Treatment, and Prevention of Alzheimer Disease and Brain Injury

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