FAK, PIP5KIγ and gelsolin cooperatively mediate force-induced expression of α-smooth muscle actin

Chan, Man Khun; Arora, Pamma D.; Bozavikov, Peter; McCulloch, Christopher A.

doi:10.1242/jcs.044008

Cited by 43 publications

(34 citation statements)

References 66 publications

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“…PIP2 also plays an important role in linking actin to integrinmediated adhesion sites, a key step in agonist-induced force generation by airway smooth muscle (52,53). However, as noted above, loss of integrin α 9 on airway smooth muscle specifically…”

Section: Discussionmentioning

confidence: 95%

Integrin α9β1 in airway smooth muscle suppresses exaggerated airway narrowing

Chen¹,

Kudo²,

Rutaganira³

et al. 2012

J. Clin. Invest.

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Exaggerated contraction of airway smooth muscle is the major cause of symptoms in asthma, but the mechanisms that prevent exaggerated contraction are incompletely understood. Here, we showed that integrin α 9 β 1 on airway smooth muscle localizes the polyamine catabolizing enzyme spermidine/spermine N 1 -acetyltransferase (SSAT) in close proximity to the lipid kinase PIP5K1γ. As PIP5K1γ is the major source of PIP2 in airway smooth muscle and its activity is regulated by higher-order polyamines, this interaction inhibited IP3-dependent airway smooth muscle contraction. Mice lacking integrin α 9 β 1 in smooth muscle had increased airway responsiveness in vivo, and loss or inhibition of integrin α 9 β 1 increased in vitro airway narrowing and airway smooth muscle contraction in murine and human airways. Contraction was enhanced in control airways by the higher-order polyamine spermine or by cell-permeable PIP2, but these interventions had no effect on airways lacking integrin α 9 β 1 or treated with integrin α 9 β 1 -blocking antibodies. Enhancement of SSAT activity or knockdown of PIP5K1γ inhibited airway contraction, but only in the presence of functional integrin α 9 β 1 . Therefore, integrin α 9 β 1 appears to serve as a brake on airway smooth muscle contraction by recruiting SSAT, which facilitates local catabolism of polyamines and thereby inhibits PIP5K1γ. Targeting key components of this pathway could thus lead to new treatment strategies for asthma.

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Section: Discussionmentioning

confidence: 95%

Integrin α9β1 in airway smooth muscle suppresses exaggerated airway narrowing

Chen¹,

Kudo²,

Rutaganira³

et al. 2012

J. Clin. Invest.

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“…Focal adhesion proteins that physically couple actin filaments to integrins and mediate transmembrane mechanical force transmission, including talin, paxillin, filamin A and vinculin, also act as mechanotransducers, in part by regulating cytoskeletal tension (Chan et al, 2009;Riveline et al, 2001). Part of this response is mediated by regulating the physical strength of the focal adhesion that resists cell traction forces to sustain cytoskeletal prestress (Fig.…”

Section: The Cytoskeleton As a Regulator Of Transcriptionmentioning

confidence: 99%

Mechanosensitive mechanisms in transcriptional regulation

Mammoto

Ingber

2012

Journal of Cell Science

336

281

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SummaryTranscriptional regulation contributes to the maintenance of pluripotency, self-renewal and differentiation in embryonic cells and in stem cells. Therefore, control of gene expression at the level of transcription is crucial for embryonic development, as well as for organogenesis, functional adaptation, and regeneration in adult tissues and organs. In the past, most work has focused on how transcriptional regulation results from the complex interplay between chemical cues, adhesion signals, transcription factors and their co-regulators during development. However, chemical signaling alone is not sufficient to explain how three-dimensional (3D) tissues and organs are constructed and maintained through the spatiotemporal control of transcriptional activities. Accumulated evidence indicates that mechanical cues, which include physical forces (e.g. tension, compression or shear stress), alterations in extracellular matrix (ECM) mechanics and changes in cell shape, are transmitted to the nucleus directly or indirectly to orchestrate transcriptional activities that are crucial for embryogenesis and organogenesis. In this Commentary, we review how the mechanical control of gene transcription contributes to the maintenance of pluripotency, determination of cell fate, pattern formation and organogenesis, as well as how it is involved in the control of cell and tissue function throughout embryogenesis and adult life. A deeper understanding of these mechanosensitive transcriptional control mechanisms should lead to new approaches to tissue engineering and regenerative medicine. IntroductionTissue and organ architecture are constructed as a result of the complex orchestration of various cell types that exhibit specific behaviors (e.g. growth, differentiation, migration and apoptosis) in specific locations at precise times during embryogenesis. Transcriptional programs confer and maintain cellular identity and functions that are necessary for the maturation of embryonic cells into terminally differentiated tissues or organs, as well as for stem cell fate switching throughout adult life. These behaviors are regulated by turning genes on and off in a highly spatiotemporally controlled manner, and this process is mediated at the level of gene transcription through the interplay between RNA polymerase II, various transcription factors and their co-regulators (Box 1). Whereas most studies on transcriptional regulation have focused on genetic or chemical control mechanisms of transcription, recent work suggests that mechanical forces (Box 2) are equally important regulators of transcriptional control in embryonic and adult tissues. In this Commentary, we review these new insights into cellular mechanotransduction, and discuss how mechanical cues influence transcriptional regulation to govern organogenesis and to ensure tissue maintenance throughout adult life.

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“…Relative Contribution of mDia in SMA Expression-In addition to the effect of mDia on force-induced SMA transcription shown above, previous studies have also established roles for gelsolin and ROCK in regulating SMA expression (8,10). To determine the relative contribution of each of these pathways on force-induced expression of SMA, we compared the effects of reducing the expression of gelsolin, ROCK and mDia on force-induced SMA promoter activity.…”

Section: Resultsmentioning

confidence: 98%

“…Cells-Human embryonic kidney (HEK-293) cells or human gingival fibroblasts (HGF; passages [5][6][7][8][9][10][11][12] were cultured at 37°C in complete DME medium containing 10% fetal bovine serum and a 1:10 dilution of an antibiotic solution (0.17% w/v penicillin V, 0.1% gentamycin sulfate, and 0.01% g/ml amphotericin). Cells were maintained in a humidified incubator gassed with 95% air and 5% CO 2 , and were passaged with 0.01% trypsin (Invitrogen, Burlington, ON).…”

Section: Methodsmentioning

confidence: 99%

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Force-induced Myofibroblast Differentiation through Collagen Receptors Is Dependent on Mammalian Diaphanous (mDia)

Chan

Chaudary

Wilson

et al. 2010

Journal of Biological Chemistry

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The development of fibrosis promotes the differentiation of myofibroblasts, pro-fibrotic cells, which contribute to tissue dysfunction. Myofibroblast differentiation is dependent on actin assembly, which in response to force, is mediated by various actin-binding proteins including the mammalian Diaphanous-related formins (mDia). We examined the role of mDia in the mechano-sensing pathway that leads to force-induced expression of ␣-smooth muscle actin (SMA), a marker and critical determinant of myofibroblast differentiation. In cells treated with siRNA to knockdown mDia and then subjected to tensile force using collagen-coated magnetite beads attached to ␤1 integrins, actin assembly was inhibited at bead contact sites. Force-induced nuclear translocation of MRTF-A, a transcriptional co-activator of SMA, was reduced 50% by mDia knockdown. The expression of the transcriptional co-activator of SMA, serum response factor, was reduced by 50% after siRNA knockdown of mDia or by 100% in cells transfected with catalytically inactive mDia. Force-induced activation of the SMA promoter and SMA expression were blocked by knockdown of siRNA of mDia. In anchored collagen gel assays to measure myofibroblast-mediated contraction, knockdown of mDia reduced contraction by 50%. We conclude that mDia plays an important role in the development of force-induced transcriptional activation of SMA and myofibroblast differentiation.During the development of fibrosis in heart, skin, liver, and kidney, fibroblasts are activated to become myofibroblasts (1). These cells strongly express ␣-smooth muscle actin (SMA) 3 and secrete abundant, disorganized collagen (2, 3), and other extracellular matrix molecules (4). Fibroblasts adhere to extracellular matrices through integrins (5, 6), cell surface receptors that provide sites for force transfer to the actin cytoskeleton and that are required for force-induced stimulation of SMA expression and myofibroblast differentiation (7). At sites of force transfer, focal adhesion proteins act as proximal sensors (8, 9) for translating mechanical forces into the signals that activate the Rho pathway (10). As a result, actin assembly is triggered (8), and there is enhanced nuclear translocation of the SMA transcriptional co-activator, myocardin-related transcription factor-A (MRTF-A) (10). Previous studies have shown that Rho signaling regulates the nuclear translocation of MRTF-A (11). Currently, the mechanisms by which force application regulates actin assembly that leads to myofibroblast differentiation are not well-defined.Actin assembly is regulated by formin proteins, which are involved in many cytoskeletal processes such as cytokinesis, actin stress fiber formation, neurite outgrowth, and intracellular trafficking (12). Members of a subfamily of formins, the mammalian Diaphanous-related formins (mDia), interact with activated, GTP-bound Rho family small GTPases. Interactions between Rho and mDia disrupt the binding of the Rho-binding domain to the diaphanous autoregulatory domain in formins, thereby ...

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FAK, PIP5KIγ and gelsolin cooperatively mediate force-induced expression of α-smooth muscle actin

Cited by 43 publications

References 66 publications

Integrin α9β1 in airway smooth muscle suppresses exaggerated airway narrowing

Integrin α9β1 in airway smooth muscle suppresses exaggerated airway narrowing

Mechanosensitive mechanisms in transcriptional regulation

Force-induced Myofibroblast Differentiation through Collagen Receptors Is Dependent on Mammalian Diaphanous (mDia)

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