Force-induced apoptosis mediated by the Rac/Pak/p38 signalling pathway is regulated by filamin A

Shifrin, Yulia; Pinto, Vanessa I.; Hassanali, Abbas; Arora, Pamma D.; McCulloch, Christopher A.

doi:10.1042/bj20112119

Cited by 23 publications

(20 citation statements)

References 47 publications

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“…In vascular endothelial cells Pak2 was suggested to be a proinflammatory factor in atherogenesis through its matrix-specific activation of JNK and NF-kB and resulting increase in vascular permeability in response to shear (Funk et al, 2010;Iliev et al, 2009;Orr et al, 2007;Orr et al, 2008). Pak1 mediated actin cytoskeleton reorganization in sheared pulmonary endothelial cells (Birukov et al, 2002) and apoptosis in response to tensile forces in NIH3T3 and HEK cells (Shifrin et al, 2012). The role of Pak1 in the MC response to stretch and in matrix upregulation remain undefined and are addressed by our studies.…”

Section: Introductionmentioning

confidence: 77%

“…No studies have examined the role of Pak1 in MC, but Pak isoforms were shown to be activated in response to mechanical signals (Iliev et al, 2009;Shifrin et al, 2012). In vascular endothelial cells Pak2 was suggested to be a proinflammatory factor in atherogenesis through its matrix-specific activation of JNK and NF-kB and resulting increase in vascular permeability in response to shear (Funk et al, 2010;Iliev et al, 2009;Orr et al, 2007;Orr et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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TGFβ receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells

Chen

Sukumar

et al. 2013

Journal of Cell Science

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SummaryIncreased intraglomerular pressure is an important pathogenic determinant of kidney fibrosis in the progression of chronic kidney disease, and can be modeled by exposing glomerular mesangial cells (MC) to mechanical stretch. MC produce extracellular matrix and profibrotic cytokines, including connective tissue growth factor (CTGF) when stretched. We show that p21-activated kinase 1 (Pak1) is activated by stretch in MC in culture and in vivo in a process marked by elevated intraglomerular pressures. Its activation is essential for CTGF upregulation. Rac1 is an upstream regulator of Pak1 activation. Stretch induces transactivation of the type I transforming growth factor b1 receptor (TbRI) independently of ligand binding. TbRI transactivation is required not only for Rac1/Pak1 activation, but also for activation of the canonical TGFb signaling intermediate Smad3. We show that Smad3 activation is an essential requirement for CTGF upregulation in MC under mechanical stress. Pak1 regulates Smad3 C-terminal phosphorylation and transcriptional activation. However, a second signaling pathway, that of RhoA/Rho-kinase and downstream Erk activation, is also required for stretch-induced CTGF upregulation in MC. Importantly, this is also regulated by Pak1. Thus, Pak1 serves as a novel central mediator in the stretchinduced upregulation of CTGF in MC.

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Section: Introductionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

TGFβ receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells

Chen

Sukumar

et al. 2013

Journal of Cell Science

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“…More recent data indicate that FLNa is required for β1 integrin activation at the outset of cell spreading on collagen, possibly by promoting the trafficking and cell surface expression of β1 integrin (23, 24). Notably, we found that FLNa is involved in the prevention of forced‐induced apoptosis through the Rac/Pak/p38 signaling pathway (25) and may play a mechanoprotective role in response to applied tensile forces.…”

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confidence: 99%

Filamin A protects cells against force‐induced apoptosis by stabilizing talin‐ and vinculin‐containing cell adhesions

et al. 2013

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In mechanically loaded tissues such as weight-bearing joints, myocardium, and periodontal ligament, pathophysiological forces can disrupt cell-matrix contacts, which can induce cell death, leading to tissue and organ dysfunction. Protection against force-induced cell death may be mediated by filamin A (FLNa), an actin-binding protein that regulates β1 integrin-mediated cell adhesion. We examined the affect of filamin expression on collagen distribution and cell death in the periodontal ligament, a force-loaded tissue. Conditional deletion of FLNa in fibroblasts was associated with 2-fold increase of acellular areas in periodontal ligament and 7-fold higher proportions of apoptotic cells. In cultured fibroblasts with FLNa knockdown, we examined the affect of supraphysiological forces (1 pN/μm(2) cell area; applied through the β1 integrin) on recruitment of talin and vinculin to focal adhesions and on apoptosis. Compared with the wild type, FLNa-knockdown cells exhibited 3-fold increases in floating cells after overnight force application and a 2-fold increase in cell detachment. Force induced time-dependent reductions (P<0.05) in the numbers of activated β1 integrin-, talin-, and vinculin-stained adhesions in FLNa-knockdown compared with those in wild-type cells. We conclude that FLNa protects against apoptosis in force-loaded cells, and this protection is mediated by enhanced formation and maturation of matrix adhesions.

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“…38,59 P38 signaling is also important for luminal epithelial cell apoptosis and P38 is a well-known target of Rac1 molecule. 41,[60][61][62] Nonetheless, it is conceivable that a tightly regulated TNFα-Rac1-P38 signaling cascade is essential for uterine luminal epithelium clearance during postimplantation uterine development.…”

Section: Discussionmentioning

confidence: 99%

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

Wang

Cui

et al. 2015

Cell Death Differ

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Successful embryo implantation requires functional luminal epithelia to establish uterine receptivity and blastocyst-uterine adhesion. During the configuration of uterine receptivity from prereceptive phase, the luminal epithelium undergoes dynamic membrane reorganization and depolarization. This timely regulated epithelial membrane maturation and precisely maintained epithelial integrity are critical for embryo implantation in both humans and mice. However, it remained largely unexplored with respect to potential signaling cascades governing this functional epithelial transformation prior to implantation. Using multiple genetic and cellular approaches combined with uterine conditional Rac1 deletion mouse model, we demonstrated herein that Rac1, a small GTPase, is spatiotemporally expressed in the periimplantation uterus, and uterine depletion of Rac1 induces premature decrease of epithelial apical-basal polarity and defective junction remodeling, leading to disrupted uterine receptivity and implantation failure. Further investigations identified Pak1-ERM as a downstream signaling cascade upon Rac1 activation in the luminal epithelium necessary for uterine receptivity. In addition, we also demonstrated that Rac1 via P38 MAPK signaling ensures timely epithelial apoptotic death at postimplantation. Besides uncovering a potentially important molecule machinery governing uterine luminal integrity for embryo implantation, our finding has high clinical relevance, because Rac1 is essential for normal endometrial functions in women. The implantation of the blastocyst into the maternal uterus is a crucial step in establishing pregnancy and thus ensuring further embryonic development. 1-3 Similar to many developmental processes, implantation involves an intricate succession of molecular and cellular interactions which must be executed within an optimal time frame. During this period, the acquisition of blastocyst implantation competency is synchronized with the establishment of uterine receptivity. [4][5][6] On the basis of previous findings, uterine sensitivity to implantationcompetent blastocysts is classically divided into three stages: pre-receptive, receptive and refractory phases. 7 In mice, prior to day 4 of pregnancy, the uterus is conventionally considered as the pre-receptive phase. On day 4 and beyond, the uterus becomes fully receptive following the priming actions of ovarian progesterone and preimplantation estrogen; whereas by late day 5, the uterus becomes refractory to initiate the implantation. 2,4,8 Upon entering the receptive phase, uterine luminal epithelium undergoes dynamic transformation. For example, on day 4 morning in mice, luminal epithelial cells cease proliferation under the dominance of increasing levels of ovarian progesterone and preimplantation estrogen. Meanwhile, the epithelial cells undergo differentiation, accompanied with a dynamic junction complex remodeling and membrane maturation, leading to a decrease of epithelial polarity approaching implantation and a cell-shape transition from...

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Force-induced apoptosis mediated by the Rac/Pak/p38 signalling pathway is regulated by filamin A

Cited by 23 publications

References 47 publications

TGFβ receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells

TGFβ receptor I transactivation mediates stretch-induced Pak1 activation and CTGF upregulation in mesangial cells

Filamin A protects cells against force‐induced apoptosis by stabilizing talin‐ and vinculin‐containing cell adhesions

Uterine RAC1 via Pak1-ERM signaling directs normal luminal epithelial integrity conducive to on-time embryo implantation in mice

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