S100 Proteins Modulate Protein Phosphatase 5 Function

Yamaguchi, Fuminori; Umeda, Yoshinori; Shimamoto, Seiko; Tsuchiya, Masaharu; Tokumitsu, Hiroshi; Tokuda, Masaaki; Kobayashi, Ryōji

doi:10.1074/jbc.m111.329771

Cited by 59 publications

(20 citation statements)

References 40 publications

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“…However, PP5 is activated when Hsp90, Ca 2+ /S100 proteins, arachidonic acid or LCACE bind to the enzyme (Fig. 8 ), to release the autoinhibitory mechanism 20 – 23 . Our work now demonstrates an important role for this distinctly regulated phosphatase in cardiomyocytes, in that it binds and specifically dephosphorylates the N2Bus spring element in cardiac titin, thus acting antagonistic to the PKs that phosphorylate N2Bus and lower cardiomyocyte passive tension.…”

Section: Discussionmentioning

confidence: 99%

“…PP5 is unique among serine/threonine phosphatases as it contains a tetratricopeptide repeat (TPR) domain at the N-terminus, which binds to the C-terminal catalytic domain and blocks substrate access to the catalytic site, such that ‘free’ PP5 has low activity 18 , 19 . However, PP5 becomes activated when the autoinhibitory mechanism is released by interaction of the TPR region with Ca 2+ /S100 proteins 20 or heat-shock protein 90 (Hsp90) 21 , 22 . Activation is also possible through binding of polyunsaturated fatty acids (e.g., arachidonic acid) or long chain fatty acid-CoA esters (LCACE) 23 .…”

Section: Introductionmentioning

confidence: 99%

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Protein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes

et al. 2018

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Serine/threonine protein phosphatase 5 (PP5) is ubiquitously expressed in eukaryotic cells; however, its function in cardiomyocytes is unknown. Under basal conditions, PP5 is autoinhibited, but enzymatic activity rises upon binding of specific factors, such as the chaperone Hsp90. Here we show that PP5 binds and dephosphorylates the elastic N2B-unique sequence (N2Bus) of titin in cardiomyocytes. Using various binding and phosphorylation tests, cell-culture manipulation, and transgenic mouse hearts, we demonstrate that PP5 associates with N2Bus in vitro and in sarcomeres and is antagonistic to several protein kinases, which phosphorylate N2Bus and lower titin-based passive tension. PP5 is pathologically elevated and likely contributes to hypo-phosphorylation of N2Bus in failing human hearts. Furthermore, Hsp90-activated PP5 interacts with components of a sarcomeric, N2Bus-associated, mechanosensor complex, and blocks mitogen-activated protein-kinase signaling in this complex. Our work establishes PP5 as a compartmentalized, well-controlled phosphatase in cardiomyocytes, which regulates titin properties and kinase signaling at the myofilaments.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes

et al. 2018

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“…Little is known about cardiac functions of PP5. Recently, it was reported that S100 proteins can modulate PP5 functions [11] and S100A1 that amongst others interacts with the cardiac ryanodine receptor and the Ca 2+ ATPase of the sarcoplasmic reticulum (SERCA), plays an important role in the inflammatory response in cardiomyocytes [12,13]. We have previously generated and described transgenic mice with cardiac specific overexpression of PP5 and demonstrated that PP5 serves as a modulator of cardiac function [14].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of protein phosphatase 5 in the mouse heart: Reduced contractility but increased stress tolerance – Two sides of the same coin?

et al. 2019

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The pathophysiological mechanisms of sepsis-induced cardiac dysfunction are largely unknown. The Toll-like receptor 4 (TLR4) is expressed in cardiac myocytes and is involved in bacterial endotoxin-mediated inflammatory disorders. TLR4 signaling leads to activation of the nuclear factor kappa B followed by increased expression of cytokines. Several protein phosphatases including PP2Cβ, PP2A or PP1 are known to act as regulators of this signaling pathway. Here, we examined the role of PP5 for the inflammatory response to the bacterial endotoxin lipopolysaccharide in the heart using a transgenic mouse model with cardiac myocyte directed overexpression of PP5. In these transgenic mice, basal cardiac contractility was reduced, in vivo as well as in vitro , but LPS-induced cardiac dysfunction was less pronounced compared to wild type mice. Quantitative RT-PCR suggested an attenuated NF-κB signaling in the heart and cardiac expression of heat shock protein 25 (HSP25) was increased in PP5 transgenic mice. From our data we assume that PP5 increases stress tolerance of cardiac myocytes by downregulation of NF-κB signaling and upregulation of HSP25 expression.

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“…S10A6 (S100A6) . This protein was found expressed at high levels in both tumor and non-tumoral tissues, confirming the key role and leadership attributed to this protein, as calcium sensor and modulator, in sustaining many physiological processes, among which the reorganization of the actin cytoskeleton and in cell motility [ 118 ].…”

Section: Discussionmentioning

confidence: 86%

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

et al. 2017

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The present investigation has been conducted on one hundred tissue fragments of breast cancer, collected and immediately cryopreserved following the surgical resection. The specimens were selected from patients with invasive ductal carcinoma of the breast, the most frequent and potentially aggressive type of mammary cancer, with the objective to increase the knowledge of breast cancer molecular markers potentially useful for clinical applications. The proteomic screening; by 2D-IPG and mass spectrometry; allowed us to identify two main classes of protein clusters: proteins expressed ubiquitously at high levels in all patients; and proteins expressed sporadically among the same patients. Within the group of ubiquitous proteins, glycolytic enzymes and proteins with anti-apoptotic activity were predominant. Among the sporadic ones, proteins involved in cell motility, molecular chaperones and proteins involved in the detoxification appeared prevalent. The data of the present study indicates that the primary tumor growth is reasonably supported by concurrent events: the inhibition of apoptosis and stimulation of cellular proliferation, and the increased expression of glycolytic enzymes with multiple functions. The second phase of the evolution of the tumor can be prematurely scheduled by the occasional presence of proteins involved in cell motility and in the defenses of the oxidative stress. We suggest that this approach on large-scale 2D-IPG proteomics of breast cancer is currently a valid tool that offers the opportunity to evaluate on the same assay the presence and recurrence of individual proteins, their isoforms and short forms, to be proposed as prognostic indicators and susceptibility to metastasis in patients operated on for invasive ductal carcinoma of the breast.

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S100 Proteins Modulate Protein Phosphatase 5 Function

Cited by 59 publications

References 40 publications

Protein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes

Protein phosphatase 5 regulates titin phosphorylation and function at a sarcomere-associated mechanosensor complex in cardiomyocytes

Overexpression of protein phosphatase 5 in the mouse heart: Reduced contractility but increased stress tolerance – Two sides of the same coin?

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

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