Actin dynamics is rapidly regulated by the PTEN and PIP<sub>2</sub> signaling pathways leading to myocyte hypertrophy

Li, Jieli; Tanhehco, Elaine J.; Russell, Brenda

doi:10.1152/ajpheart.00393.2014

Cited by 30 publications

(28 citation statements)

References 40 publications

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“…CapZβ1 responds to neurohormonal and mechanical mechanosensing pathways and integrates their signals as we and others have suggested (Hartman et al 2009; Li and Russell 2013; Li et al 2014; Lin et al 2013). CapZ dynamics are closely correlated with actin dynamics and sarcomere assembly, thus linking the CapZ capping process to cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 70%

“…Furthermore, some PTMs cannot be measured by 2DGE because they are not associated with charge change, such as methylation or oxidation. For example, CapZ and actin dynamic regulation does occur without charge change or PTM by PIP 2 involvement in actin capping (Hartman et al 2009; Li and Russell 2013; Li et al 2014). Thus, numerous signaling pathways could contribute to the regulation of CapZ and cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

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Cyclic mechanical strain of myocytes modifies CapZβ1 post translationally via PKCε

Lin

Swanson

et al. 2015

J Muscle Res Cell Motil

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The heart is exquisitely sensitive to mechanical stimuli and adapts to increased demands for work by enlarging the cardiomyocytes. In order to determine links between mechano-transduction mechanisms and hypertrophy, neonatal rat ventricular myocytes (NRVM) were subjected to physiologic strain for analysis of the dynamics of the actin capping protein, CapZ, and its post-translational modifications (PTM). CapZ binding rates were assessed after strain by fluorescence recovery after photobleaching (FRAP) of green fluorescent protein (GFP) expressed by a GFP-CapZβ1 adenovirus. To assess the role of the protein kinase C epsilon isoform (PKCε), rest or cyclic strain were combined with specific PKCε activation by constitutively active PKCε, or by inhibition with dominant negative PKCε (dnPKCε) expression. Significant increases of CapZ FRAP kinetics with strain were blunted by dnPKCε, suggesting that PKCε is involved in mechano-transduction signaling. Similar combinations of strain and PKC regulation in NRVMs were studied by PTM profiles of CapZβ1 using quantitative two-dimensional gel electrophoresis. The significantly increased charge on CapZ seen with mechanical strain was reversed by the addition of dnPKCε. Potential clinical relevance was confirmed in vivo by PTMs of CapZ in the failing heart of one-year old transgenic mice over-expressing PKCε. Furthermore, with strain there was significant PKCε translocation to the Z-disc and co-localization with CapZβ1 or α-actinin, which was quantified on confocal images. A hypothetical model is presented proposing that one destination of the mechanotransduction signaling pathways might be for PTMs of CapZ thereby regulating actin capping and filament assembly.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Cyclic mechanical strain of myocytes modifies CapZβ1 post translationally via PKCε

Lin

Swanson

et al. 2015

J Muscle Res Cell Motil

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“…Thus, PIP2 binding may result in a reduction in binding affinity of CapZ dimers to the actin filament (Hartman et al 2009; Li and Russell 2013). We have shown that there is more PIP2 at Z-disc when the cell size is bigger (Li and Russell 2013; Li et al 2014). Both actin and CapZ dynamics were also greater with hypertrophy.…”

Section: Discussionmentioning

confidence: 85%

Variation in stiffness regulates cardiac myocyte hypertrophy via signaling pathways

Mkrtschjan

Lin

et al. 2016

Can. J. Physiol. Pharmacol.

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Much diseased human myocardial tissue is fibrotic and stiff, which increases the work that the ventricular myocytes must perform to maintain cardiac output. The hypothesis tested is that the increased load due to greater stiffness of the substrata drives sarcomere assembly of cells, thus strengthening them. Neonatal rat ventricular myocytes (NRVM) were cultured on polyacrylamide or polydimethylsiloxane substrates with stiffness of 10 kPa, 100 kPa, or 400 kPa, or glass with stiffness of 61.9 GPa. Cell size increased with stiffness. Two signaling pathways were explored, phosphorylation of focal adhesion kinase (p-FAK) and lipids by phosphatidylinositol 4,5-bisphosphate (PIP2). Subcellular distributions of both were determined in the sarcomeric fraction by antibody localization, and total amounts were measured by Western or dot blotting, respectively. More p-FAK and PIP2 distributed to the sarcomeres of NRVM grown on stiffer substrates. Actin assembly involves the actin capping protein Z (CapZ). Both actin and CapZ dynamic exchange were significantly increased on stiffer substrates when assessed by fluorescence recovery after photobleaching (FRAP) of green fluorescent protein tags. Blunting of actin FRAP by FAK inhibition implicates linkage from mechano-signalling pathways to cell growth. Thus, increased stiffness of cardiac disease can be modeled with polymeric materials to understand how the microenvironment regulates cardiac hypertrophy.

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“…Upon mechanical stimulation of CMs, assembly may be controlled in an hour by an acute bout of activity through modification of the actin capping protein, CapZ, where load increases actin dynamics, filament assembly, and cell size (Lin et al, ). Mechanotransduction arising from stress or strain modifies the function of CapZ by phosphorylation via protein kinase C (PKC) (Disatnik, Buraggi, & Mochly‐Rosen, ; Kim, Cooper, & Sept, ; Wear & Cooper, ) , lipid binding with phosphatidylinositol 4,5‐bisphosphate (PIP2) (Hartman, Martin, Solaro, Samarel, & Russell, ; Li & Russell, ; Li, Tanhehco, & Russell, ), and through acetylation (Lin, Warren, Li, McKinsey, & Russell, ). Here, we concentrate on phosphorylation, which has recently been thoroughly reviewed (Scruggs, Wang, & Ping, ).…”

Section: Introductionmentioning

confidence: 99%

PKC epsilon signaling effect on actin assembly is diminished in cardiomyocytes when challenged to additional work in a stiff microenvironment

et al. 2018

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The stiffness of the microenvironment surrounding a cell can result in cytoskeletal remodeling, leading to altered cell function and tissue macrostructure. In this study, we tuned the stiffness of the underlying substratum on which neonatal rat cardiomyocytes were grown in culture to mimic normal (10 kPa), pathological stiffness of fibrotic myocardium (100 kPa), and a nonphysiological extreme (glass). Cardiomyocytes were then challenged by beta adrenergic stimulation through isoproterenol treatment to investigate the response to acute work demand for cells grown on surfaces of varying stiffness. In particular, the PKCɛ signaling pathway and its role in actin assembly dynamics were examined. Significant changes in contractile metrics were seen on cardiomyocytes grown on different surfaces, but all cells responded to isoproterenol treatment, eventually reaching similar time to peak tension. In contrast, the assembly rate of actin was significantly higher on stiff surfaces, so that only cells grown on soft surfaces were able to respond to acute isoproterenol treatment. Förster Resonance Energy Transfer of immunofluorescence on the cytoskeletal fraction of cardiomyocytes confirmed that the molecular interaction of PKCɛ with the actin capping protein, CapZ, was very low on soft substrata but significantly increased with isoproterenol treatment, or on stiff substrata. Therefore, the stiffness of the culture surface chosen for in vitro experiments might mask the normal signaling and affect the ability to translate basic science more effectively into human therapy.

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Actin dynamics is rapidly regulated by the PTEN and PIP₂ signaling pathways leading to myocyte hypertrophy

Abstract: Li J, Tanhehco EJ, Russell B. Actin dynamics is rapidly regulated by the PTEN and PIP2 signaling pathways leading to myocyte hypertrophy.

Cited by 30 publications

References 40 publications

Cyclic mechanical strain of myocytes modifies CapZβ1 post translationally via PKCε

Cyclic mechanical strain of myocytes modifies CapZβ1 post translationally via PKCε

Variation in stiffness regulates cardiac myocyte hypertrophy via signaling pathways

PKC epsilon signaling effect on actin assembly is diminished in cardiomyocytes when challenged to additional work in a stiff microenvironment

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