The p90 Ribosomal S6 Kinase (RSK) Is a Mediator of Smooth Muscle Contractility

Artamonov, Mykhaylo V.; Momotani, Ko; Utepbergenov, Darkhan; Franke, Aaron S.; Khromov, Alexander S.; Derewenda, Zygmunt S.; Somlyo, Avril V.

doi:10.1371/journal.pone.0058703

Cited by 15 publications

(22 citation statements)

References 50 publications

(66 reference statements)

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“…21, 37 In our current work, we report that β-arrestin signaling increases ERK1/2 phosphorylation as well as RSK3 phosphorylation, signaling to MLC2v. The role of the RSK family members in the development and maintenance of cardiac disease is not understood.…”

Section: Discussionmentioning

confidence: 53%

Long-Term Biased β-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy

Ryba

Cowan

et al. 2017

Circulation

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Background Biased agonism of the angiotensin receptor (AT1R) is known to promote cardiac contractility. Our laboratory indicated that these effects may be due to changes at the level of the myofilaments. However, these signaling mechanisms remain unknown. As a common finding in dilated cardiomyopathy (DCM) is a reduction in the myofilament-Ca2+-response, we hypothesized that β-arrestin signaling would increase myofilament-Ca2+-responsiveness in a model of familial DCM and improve cardiac function and morphology. Methods We treated a DCM-linked mouse model expressing a mutant tropomyosin (Tm-E54K), for three months with either TRV120067, a β-arrestin 2 biased ligand of the AT1R, or losartan, an AT1R blocker. At the end of the treatment protocol, we assessed cardiac function using echocardiography, the myofilament-Ca2+-response of detergent-extracted fiber bundles, and used proteomic approaches to understand changes in post-translational modifications of proteins that may explain functional changes. We also assessed signaling pathways altered in vivo and using isolated myocytes. Results TRV120067- treated Tm-E54K mice showed improved cardiac structure and function, whereas losartan-treated mice had no improvement. Myofilaments of TRV120067-treated Tm-E54K mice had significantly improved myofilament-Ca2+-responsiveness, which was depressed in untreated Tm-E54K mice. We attributed these changes to increased MLC2v and MYPT1/2 phosphorylation seen only in TRV120067-treated mice. We found that the functional changes were due to an activation of ERK1/2-RSK3 signaling, mediated through β-arrestin, which may have a novel role in increasing MLC2v phosphorylation through a previously unrecognized interaction of β-arrestin localized to the sarcomere. Conclusions Long-term β-arrestin 2 biased agonism of the AT1R may be a viable approach to the treatment of DCM by not only preventing maladaptive signaling, but also improving cardiac function by altering the myofilament-Ca2+-response via β-arrestin signaling pathways.

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Section: Discussionmentioning

confidence: 53%

Long-Term Biased β-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy

Ryba

Cowan

et al. 2017

Circulation

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“…Myricetin can be used as a health food on account of its anti-tumor characteristics. Ribosomal S6 kinase (RSK) 2 is a member of the p90RSK protein family, and it can be translocated when activated by neurotransmitters or growth factors [6,7]. Also, RSK2 is involved in many cellular processes, such as proliferation, cell cycle, and apoptosis [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Myricetin inhibits proliferation and induces apoptosis and cell cycle arrest in gastric cancer cells

et al. 2015

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Myricetin is a flavonoid that is abundant in fruits and vegetables and has protective effects against cancer and diabetes. However, the mechanism of action of myricetin against gastric cancer (GC) is not fully understood. We researched myricetin on the proliferation, apoptosis, and cell cycle in GC HGC-27 and SGC7901 cells, to explore the underlying mechanism of action. Cell Counting Kit (CCK)-8 assay, Western blotting, cell cycle analysis, and apoptosis assay were used to evaluate the effects of myricetin on cell proliferation, apoptosis, and the cell cycle. To analyze the binding properties of ribosomal S6 kinase 2 (RSK2) with myricetin, surface plasmon resonance (SPR) analysis was performed. CCK8 assay showed that myricetin inhibited GC cell proliferation. Flow cytometry analysis showed that myricetin induces apoptosis and cell cycle arrest in GC cells. Western blotting indicated that myricetin influenced apoptosis and cell cycle arrest of GC cells by regulating related proteins. SPR analysis showed strong binding affinity of RSK2 and myricetin. Myricetin bound to RSK2, leading to increased expression of Mad1, and contributed to inhibition of HGC-27 and SGC7901 cell proliferation. Our results suggest the therapeutic potential of myricetin in GC.

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“…It has been reported that p90RSK is activated by ERK signal, leading to actin polymerization . It is also demonstrated that activation of p90RSK facilitates SMC contraction . In human aortic smooth muscle, inhibition of MEK/ERK/Elk‐1(ETS transcription factor‐1) and p90RSK pathways reduces both cell proliferation and migration .…”

Section: Discussionmentioning

confidence: 99%

Responses of bladder smooth muscle to the stretch go through extracellular signal‐regulated kinase (ERK)/p90 ribosomal S6 protein kinase (p90RSK)/Nuclear factor‐κB (NF‐κB) Pathway

Lin

et al. 2019

Neurourology and Urodynamics

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Aims The present study was designed to study changes and its potential mechanisms in human bladder smooth muscle subjected to stretch. Methods Bioinformatics analyses including differential expression analysis, overrepresentation enrichment analysis, principal component analysis, and weighted gene coexpression network analysis were used to analyze a microarray dataset (GSE47080) of partial bladder outlet obstruction (pBOO) in rat to find the potential changes of gene expressions. Bladder from pBOO model and human bladder smooth muscle cells (HBSMCs) subjected to sustained prolonged stretch were collected for Western blot analysis, real‐time polymerase chain reaction, and fluorescence analysis to verify the changes of gene expressions and preliminarily study the potential role of signaling pathway regulation in treatment of pBOO. Results The bioinformatics analysis showed that chronic obstruction activated mitogen‐activated protein kinase pathway and changed cytoskeleton structure in bladder smooth muscle. In in vivo experiments in mice, pBOO was verified by cystometry. Partial BOO activated the extracellular signal‐regulated kinase (ERK)/p90 ribosomal S6 protein kinase (p90RSK)/nuclear factor‐κB (NF‐κB) signaling pathway in DM. The messenger RNA (mRNA) expressions of contractile phenotypic proteins increased after pBOO. In in vitro experiments of HBSMCs, mechanical stretch activated ERK/p90RSK/NF‐κB in HBSMCs in a time‐dependent manner. The mRNA expressions of α‐smooth muscle actin and SM22 also increased and filamentous actin (F‐actin) polymerization was enhanced as well. Inhibition of ERK/p90RSK/NF‐κB pathway reversed mechanical stretch‐induced changes of contractile phenotypic expression and F‐action polymerization. Conclusions Continuous stretch increases expressions of contractile phenotypic proteins and promotes the polymerization of F‐actin. This process partially goes through ERK/p90RSK/NF‐κB pathway.

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The p90 Ribosomal S6 Kinase (RSK) Is a Mediator of Smooth Muscle Contractility

Cited by 15 publications

References 50 publications

Long-Term Biased β-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy

Long-Term Biased β-Arrestin Signaling Improves Cardiac Structure and Function in Dilated Cardiomyopathy

Myricetin inhibits proliferation and induces apoptosis and cell cycle arrest in gastric cancer cells

Responses of bladder smooth muscle to the stretch go through extracellular signal‐regulated kinase (ERK)/p90 ribosomal S6 protein kinase (p90RSK)/Nuclear factor‐κB (NF‐κB) Pathway

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