CapZ integrates several signaling pathways in response to mechanical stiffness

Solı́s, Christopher; Russell, Brenda

doi:10.1085/jgp.201812199

Cited by 15 publications

(16 citation statements)

References 47 publications

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“…Among the target transcripts and proteins affected in DMSXL astrocytes, CAPZB and PALM regulate cell morphology and differentiation, through their interaction with the actin-cytoskeleton and sites of plasma membrane activity (e.g., filopodia), respectively ( Arstikaitis et al, 2008 ; Mukherjee et al, 2016 ). Both proteins show alternative splicing and phosphorylation-dependent activity ( Kutzleb et al, 1998 ; Solís and Russell, 2019 ). Extensive prenylation and palmitoylation have been reported in PALM, contributing to the complex electrophoretic profiles ( Kutzleb et al, 1998 ).…”

Section: Discussionmentioning

confidence: 99%

Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1

González-Barriga

Lallemant

Dincã

et al. 2021

Front. Cell. Neurosci.

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Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a non-coding CTG repeat expansion in the DMPK gene. This mutation generates a toxic CUG RNA that interferes with the RNA processing of target genes in multiple tissues. Despite debilitating neurological impairment, the pathophysiological cascade of molecular and cellular events in the central nervous system (CNS) has been less extensively characterized than the molecular pathogenesis of muscle/cardiac dysfunction. Particularly, the contribution of different cell types to DM1 brain disease is not clearly understood. We first used transcriptomics to compare the impact of expanded CUG RNA on the transcriptome of primary neurons, astrocytes and oligodendrocytes derived from DMSXL mice, a transgenic model of DM1. RNA sequencing revealed more frequent expression and splicing changes in glia than neuronal cells. In particular, primary DMSXL oligodendrocytes showed the highest number of transcripts differentially expressed, while DMSXL astrocytes displayed the most severe splicing dysregulation. Interestingly, the expression and splicing defects of DMSXL glia recreated molecular signatures suggestive of impaired cell differentiation: while DMSXL oligodendrocytes failed to upregulate a subset of genes that are naturally activated during the oligodendroglia differentiation, a significant proportion of missplicing events in DMSXL oligodendrocytes and astrocytes increased the expression of RNA isoforms typical of precursor cell stages. Together these data suggest that expanded CUG RNA in glial cells affects preferentially differentiation-regulated molecular events. This hypothesis was corroborated by gene ontology (GO) analyses, which revealed an enrichment for biological processes and cellular components with critical roles during cell differentiation. Finally, we combined exon ontology with phosphoproteomics and cell imaging to explore the functional impact of CUG-associated spliceopathy on downstream protein metabolism. Changes in phosphorylation, protein isoform expression and intracellular localization in DMSXL astrocytes demonstrate the far-reaching impact of the DM1 repeat expansion on cell metabolism. Our multi-omics approaches provide insight into the mechanisms of CUG RNA toxicity in the CNS with cell type resolution, and support the priority for future research on non-neuronal mechanisms and proteomic changes in DM1 brain disease.

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Section: Discussionmentioning

confidence: 99%

Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1

González-Barriga

Lallemant

Dincã

et al. 2021

Front. Cell. Neurosci.

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“…Despite enhanced calcium dynamics and contractility upon the loss of PI3Kγ in cardiac myocytes, decompensation ensues because of dysregulated cellular-ECM interactions (Guo et al, 2010). Furthermore, a more direct relationship between PI3Kγ and cardiac mechanotransduction (Kalwa and Michel, 2011) Rac involved in numerous mechanotransduction pathways (i.e., FAK-Cas-Rac axis) (Labouesse, 2011;Lawson and Burridge, 2014;McGowan and McCoy, 2017) PIP 2 CapZ Ventricular CMs (Solis and Russell, 2019) PIP 2 acts as a mechanical sensor at sarcomere Z-disc in response to mechanical stimuli (Solis and Russell, 2019) Sarcomere Z-disc located on CapZβ1 is a site for mechanotransduction (Russell et al, 2010) PIP 2 and PKC TRPC1 VSMCs (Saleh et al, 2009b;Shi et al, 2012;Baudel et al, 2020) Functions are associated with the development of vascular diseases (Saleh et al, 2009b;Shi et al, 2012;Baudel et al, 2020) TRPC1 is implicated in mechanotransduction (Formigli et al, 2009;Garrison et al, 2012;Canales et al, 2019; PIP 2 Kir2.1 and TRPV4…”

Section: Pip 3 Pi3kα and Pi3kγ Association With Mechanotransductiomentioning

confidence: 99%

“…CapZ is modified by the stimuli’s signaling pathways through phosphorylation, acetylation or PIP 2 binding. Thus, an actin assembly mechanism can be presented where phosphorylation, acetylation or PIP 2 anchorage causes CapZ to act as a nodal terminus for the integration of various signaling pathways ( Solis and Russell, 2019 ). This mechanism implicates PIP 2 as a critical mediator of mechanotransduction in cardiac myocytes by directly affecting CapZ in response to mechanical stiffness.…”

Section: Phosphatidylinositol-45-bisphosphate (Pip 2 mentioning

confidence: 99%

Phosphoinositide Signaling and Mechanotransduction in Cardiovascular Biology and Disease

Krajnik

Brazzo

Vaidyanathan

et al. 2020

Front. Cell Dev. Biol.

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Phosphoinositides, which are membrane-bound phospholipids, are critical signaling molecules located at the interface between the extracellular matrix, cell membrane, and cytoskeleton. Phosphoinositides are essential regulators of many biological and cellular processes, including but not limited to cell migration, proliferation, survival, and differentiation, as well as cytoskeletal rearrangements and actin dynamics. Over the years, a multitude of studies have uniquely implicated phosphoinositide signaling as being crucial in cardiovascular biology and a dominant force in the development of cardiovascular disease and its progression. Independently, the cellular transduction of mechanical forces or mechanotransduction in cardiovascular cells is widely accepted to be critical to their homeostasis and can drive aberrant cellular phenotypes and resultant cardiovascular disease. Given the versatility and diversity of phosphoinositide signaling in the cardiovascular system and the dominant regulation of cardiovascular cell functions by mechanotransduction, the molecular mechanistic overlap and extent to which these two major signaling modalities converge in cardiovascular cells remain unclear. In this review, we discuss and synthesize recent findings that rightfully connect phosphoinositide signaling to cellular mechanotransduction in the context of cardiovascular biology and disease, and we specifically focus on phosphatidylinositol-4,5-phosphate, phosphatidylinositol-4-phosphate 5-kinase, phosphatidylinositol-3,4,5-phosphate, and phosphatidylinositol 3-kinase. Throughout the review, we discuss how specific phosphoinositide subspecies have been shown to mediate biomechanically sensitive cytoskeletal remodeling in cardiovascular cells. Additionally, we discuss the direct interaction of phosphoinositides with mechanically sensitive membrane-bound ion channels in response to mechanical stimuli. Furthermore, we explore the role of phosphoinositide subspecies in association with critical downstream effectors of mechanical signaling in cardiovascular biology and disease.

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“…By utilizing a BRET probe in the place of FRET, this DNA detection technique can be used in live animal models, thereby expanding the potential for this technique. FRET has been widely used in detecting protein-protein interactions [5,6,7,8,9,10]. One such study encountered problems in analyzing protein proximity in the endoplasmic reticulum of cells due to the overlap of the FRET emission wavelength and highly variable cellular autofluorescence [5].…”

Section: Introductionmentioning

confidence: 99%

“…QDs have the advantage of adjustable emission depending on size, superior brightness, high photostability, and multiplexing [31,32]. Fluorescent semiconductor quantum dots were previously limited in their application for in vivo imaging due to requiring excitation from an external source of light [5,6,7,8]. Combining QDs with luminescence provided by bioluminescent proteins has provided opportunities for in vivo imaging [7].…”

Section: Introductionmentioning

confidence: 99%

Integration of Nanomaterials and Bioluminescence Resonance Energy Transfer Techniques for Sensing Biomolecules

2019

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Bioluminescence resonance energy transfer (BRET) techniques offer a high degree of sensitivity, reliability and ease of use for their application to sensing biomolecules. BRET is a distance dependent, non-radiative energy transfer, which uses a bioluminescent protein to excite an acceptor through the resonance energy transfer. A BRET sensor can quickly detect the change of a target biomolecule quantitatively without an external electromagnetic field, e.g., UV light, which normally can damage tissue. Having been developed quite recently, this technique has evolved rapidly. Here, different bioluminescent proteins have been reviewed. In addition to a multitude of bioluminescent proteins, this manuscript focuses on the recent development of BRET sensors by utilizing quantum dots. The special size-dependent properties of quantum dots have made the BRET sensing technique attractive for the real-time monitoring of the changes of target molecules and bioimaging in vivo. This review offers a look into the basis of the technique, donor/acceptor pairs, experimental applications and prospects.

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CapZ integrates several signaling pathways in response to mechanical stiffness

Cited by 15 publications

References 47 publications

Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1

Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1

Phosphoinositide Signaling and Mechanotransduction in Cardiovascular Biology and Disease

Integration of Nanomaterials and Bioluminescence Resonance Energy Transfer Techniques for Sensing Biomolecules

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