ERM proteins regulate cytoskeleton relaxation promoting T cell–APC conjugation

Faure, Sophie; Salazar-Fontana, Laura I.; Sémichon, Monique; Tybulewicz, Victor L. J.; Bismuth, Georges; Trautmann, Alain; Germain, Ronald N.; Delon, Jérôme

doi:10.1038/ni1039

Cited by 250 publications

(253 citation statements)

References 50 publications

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“…Ezrin is present in a phosphorylated form in cells before stimulation through Fas, antigen receptors or chemokine receptors, and is dephosphorylated after these stimulations (Kondo et al, 1997;Delon et al, 2001;Brown et al, 2003;Faure et al, 2004;Gupta et al, 2006;Hao et al, 2009). Our observation that ezrin was dephosphorylated after FasL stimulation in T cells (Figure 1c) is in accordance with those reports.…”

Section: Discussionsupporting

confidence: 92%

“…How ERM participates in several membrane-associated events in lymphocytes remains unclear. For example, three different roles have been reported for the involvement of ezrin-moesin in immunological synapse (IS) formation: ERM was found to be essential for the assembly of IS and the recruitment of ZAP70 in one group of studies (Roumier et al, 2001;Ilani et al, 2007); ezrin was reported to be completely dispensable for IS formation in another study (Shaffer et al, 2009); and in yet a third proposal, ezrin was also declared to negatively regulate IS formation (Faure et al, 2004). Similarly, opposite effects of ERM have been documented for T-lymphocyte movement; T-cell migration could be enhanced by either ERM phosphorylation (Li et al, 2007) or ERM dephosphorylation (Brown et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Activated ezrin and moesin are required for the formation of the distal pole complex (Allenspach et al, 2001) and for the movement of a cytotoxic cell to target cells (Mrass et al, 2008). Alternatively, lymphocyte activation and remolding involves ezrin/moesin inactivation and dissociation from cortical actin (Delon et al, 2001;Brown et al, 2003;Faure et al, 2004;Gupta et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Ezrin is a negative regulator of death receptor-induced apoptosis

et al. 2009

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Ezrin links cortical actin filaments with the cell membrane, and has a critical role in many membrane-initiated events. Fas is directly associated with ezrin, but conflicting results have been reported for the involvement of ezrin in Fas-induced cell death. In this study we show that ezrin was associated with Fas in T cells before stimulation and was released shortly after Fas ligand (FasL) engagement. The knockdown of ezrin moderately increased Fastriggered or tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-triggered cell death in normal T lymphocytes and in H9 cells, but had no effect on death receptor-induced apoptosis in type II cells, such as Jurkat and CEM. Expression of a dominant-negative form of ezrin also led to an increased Fas-induced apoptosis in H9 cells. Ezrin deficiency did not affect the internalization of Fas after Fas ligation. Instead, an enhanced formation of death-inducing signaling complex (DISC) was observed in H9 cells with ezrin knockdown, leading to accelerated caspase-8 activation. Together, our results suggest that ezrin has a negative role in the recruitment of Fas into signaling complexes in type I T cells. Loss of ezrin likely removes the constraint imposed by ezrin and facilitates the assembly of death receptor complex in T cells.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ezrin is a negative regulator of death receptor-induced apoptosis

et al. 2009

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“…No proliferation occurred in a pure CD4 + T cell population stimulated with only PHA, which emphasizes the importance of a focal stimulation and the formation of an IS for an efficient immune response [28,29]. PHA is known to act as a cross-linker molecule that binds to glycoproteins all over the cell surface.…”

Section: Discussionmentioning

confidence: 96%

Calcium dependence of T cell proliferation following focal stimulation

et al. 2007

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Clonal T cell expansion through proliferation is a central process of the adaptive immune response. Apoptosis of activated T cells is required to avoid chronic inflammation. T cell proliferation and apoptosis are often analyzed with stimuli that do not induce formation of a functional immunological synapse. Here we analyze the Ca 2+ dependence of proliferation and apoptosis in primary human CD4 + T cells following stimulation with anti-CD3/anti-CD28-coated beads, which induce a tight interaction similar to the immunological synapse. We found this focal stimulation to be much more efficient for stimulating IL-2 production and proliferation than non-focal TCR stimuli. Surprising little Ca 2+ entry through Ca 2+ channels was required for T cell proliferation. Transient free intracellular calcium concentration ([Ca 2+ ] i ) elevations of up to 220 nM from a baseline level of around 40 nM were sufficient for maximal proliferation in primary human CD4 + T cells. We also show that proliferation was very Ca 2+ sensitive in the range 90-120 nM, whereas apoptosis was basically constant for [Ca 2+ ] i levels of 90-120 nM. We conclude that very small changes in [Ca 2+ ] i can dramatically change the ratio between proliferation and apoptosis, thus keeping the balance between overshooting and inefficient immune responses.

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“…This is consistent with previous findings that ERM is essential for Rac family protein-induced cytoskeletal configuration and Rac1 can regulate ERM phosphorylation. 17,34,[53][54][55] In searching for the intermediate signaling molecule linking Rac1 activation and ERM phosphorylation, we found that Pak1, a serine/threonine kinase is a downstream target of Rac1 activation, accounts for ERM phosphorylation. It has been reported that Pak1 is involved in the phosphorylation activation of merlin, a highly homologous protein to ERM family members.…”

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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ERM proteins regulate cytoskeleton relaxation promoting T cell–APC conjugation

Cited by 250 publications

References 50 publications

Ezrin is a negative regulator of death receptor-induced apoptosis

Ezrin is a negative regulator of death receptor-induced apoptosis

Calcium dependence of T cell proliferation following focal stimulation

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

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