Biphasic Regulation of Myosin Light Chain Phosphorylation by p21-activated Kinase Modulates Intestinal Smooth Muscle Contractility

Chu, Ji; Pham, N.; Olate, Nicole; Kislitsyna, Karina; Day, M.; Letourneau, Phillip A.; Kots, Alexander Y.; Stewart, Randolph H.; Laine, Glen A.; Cox, Charles S.; Uray, Karen

doi:10.1074/jbc.m112.370718

Cited by 19 publications

(40 citation statements)

References 54 publications

(78 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The FX‐4000™ Tension System (Flexcell) was used to apply mechanical force to cells. The control cyclical stretch (CCS) and edema cyclical stretch (ECS) protocols were designed based on the spontaneous contraction amplitude and frequency measured in vivo in previous experiments . For THP‐1 cells, media was collected and used for subsequent cell and contractile activity experiments.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

CXCL1 is upregulated during the development of ileus resulting in decreased intestinal contractile activity

Docsa

Bhattarai

Sipos

et al. 2019

Neurogastroenterology Motil

Self Cite

View full text Add to dashboard Cite

Background Although the development of ileus is widespread and negatively impacts patient outcomes, the mechanism by which ileus develops remains unclear. The purpose of our study was to examine the contribution of myogenic mechanisms to postoperative ileus development and the involvement of inflammation in mediating intestinal smooth muscle dysfunction. Methods Contractile activity and the effects of CXCL1 were studied in a gut manipulation model. Key Results Contraction amplitude in the ileum decreased significantly, while tone increased significantly in response to gut manipulation. Differences in contraction amplitude were affected by tetrodotoxin at earlier time points, but not at later time points. Agonist‐induced contractions in the small intestine decreased significantly with ileus development. Intestinal transit slowed significantly after the induction of ileus. Myosin light chain phosphorylation was significantly decreased and edema increased significantly in the intestinal wall. Conditioned media from mechanically activated macrophages depressed intestinal contractile activity. CXCL1 (GroA) was significantly increased in the mechanically activated macrophages and intestinal smooth muscle within 1 hour after induction of ileus compared with control cells and sham animals, respectively. Treatment with CXCL1 significantly decreased contraction amplitude and agonist‐induced contractile activity and increased tone in the small intestine. In the gut manipulation model, treatment with a CXCR2 antagonist prevented the decrease in agonist‐induced contractile activity but not contraction amplitude. Conclusions & Inferences These data suggest that CXCL1, released from macrophages during intestinal wall stress, can suppress intestinal contractile activity. CXCL1 is a potential target for preventing or treating ileus in trauma patients.

show abstract

Section: Methodsmentioning

confidence: 99%

“…Edema development results in increased intestinal wall stress . Increased stretch of intestinal smooth muscle cells has been shown to down‐regulate MLC phosphorylation . Thus, edema‐induced mechanotransduction in the intestinal smooth muscle layers is one mechanism by which edema causes smooth muscle dysfunction.…”

Section: Introductionmentioning

confidence: 99%

CXCL1 is upregulated during the development of ileus resulting in decreased intestinal contractile activity

Docsa

Bhattarai

Sipos

et al. 2019

Neurogastroenterology Motil

Self Cite

View full text Add to dashboard Cite

show abstract

“…Other kinases such as p21-activated kinase (PAK) and P34 kinase also affect RLC phosphorylation, but most reports refer to smooth muscle and non-muscle cells (Chu et al 2013). …”

Section: In Vitro Modificationmentioning

confidence: 99%

“…For example, γ-PAK, that is activated by GTP-binding proteins Cdc42 and Rac, catalyses phosphorylation of intact non-muscle myosin-II and isolated recombinant RLC (Chu et al 2013). However, the PAK isoform of smooth muscle tissue, known as PAK1, affects RLC phosphorylation differently.…”

Section: In Vitro Modificationmentioning

confidence: 99%

Phosphorylation of the regulatory light chain of myosin in striated muscle: methodological perspectives

Chakravorty

Song

et al. 2016

Eur Biophys J

View full text Add to dashboard Cite

Phosphorylation of the regulatory light chain (RLC) of myosin modulates cellular functions such as muscle contraction, mitosis, and cytokinesis. Phosphorylation defects are implicated in a number of diseases. Here we focus on striated muscle where changes in RLC phosphorylation relate to diseases such as hypertrophic cardiomyopathy and muscular dystrophy, or age-related changes. RLC phosphorylation in smooth muscle and non-muscle cells are covered briefly where relevant. There is much scientific interest in controlling the phosphorylation levels of RLC in vivo and in vitro in order to understand its physiological function in striated muscles. A summary of available and emerging in vivo and in vitro methods is presented. The physiological role of RLC phosphorylation and novel pathways are discussed to highlight the differences between muscle types and to gain insights into disease processes.

show abstract

“…PAK4 phosphorylates myosin regulatory light chain and contributes to Fcγ receptor-mediated phagocytosis [124]. PAK1 activation can increase or decrease MLC phosphorylation in primary human intestinal smooth muscle depending on the circumstances, such as mechanical stretch, via regulation of MLC phosphatase targeting subunit [125]. Rac induces an increase in phosphorylation of myosin regulatory light chain in HeLa cells [126].…”

Section: Physiological Functions Of Pak During Inflammationmentioning

confidence: 99%

P21-activated kinase in inflammatory and cardiovascular disease

Taglieri

Ushio‐Fukai

Monasky

2014

Cellular Signalling

View full text Add to dashboard Cite

P-21 activated kinases, or PAKs, are serine–threonine kinases that serve a role in diverse biological functions and organ system diseases. Although PAK signaling has been the focus of many investigations, still our understanding of the role of PAK in inflammation is incomplete. This review consolidates what is known about PAK1 across several cell types, highlighting the role of PAK1 and PAK2 in inflammation in relation to NADPH oxidase activation. This review explores the physiological functions of PAK during inflammation, the role of PAK in several organ diseases with an emphasis on cardiovascular disease, and the PAK signaling pathway, including activators and targets of PAK. Also, we discuss PAK1 as a pharmacological anti-inflammatory target, explore the potentials and the limitations of the current pharmacological tools to regulate PAK1 activity during inflammation, and provide indications for future research. We conclude that a vast amount of evidence supports the idea that PAK is a central molecule in inflammatory signaling, thus making PAK1 itself a promising prospective pharmacological target.

show abstract

Biphasic Regulation of Myosin Light Chain Phosphorylation by p21-activated Kinase Modulates Intestinal Smooth Muscle Contractility

Cited by 19 publications

References 54 publications

CXCL1 is upregulated during the development of ileus resulting in decreased intestinal contractile activity

CXCL1 is upregulated during the development of ileus resulting in decreased intestinal contractile activity

Phosphorylation of the regulatory light chain of myosin in striated muscle: methodological perspectives

P21-activated kinase in inflammatory and cardiovascular disease

Contact Info

Product

Resources

About