MRCKα is activated by caspase cleavage to assemble an apical actin ring for epithelial cell extrusion

Gagliardi, Paolo Armando; Somale, Desiana; Puliafito, Alberto; Chiaverina, Giulia; Blasio, Laura di; Oneto, Michele; Bianchini, Paolo; Bussolino, Federico; Primo, Luca

doi:10.1083/jcb.201703044

Cited by 32 publications

(40 citation statements)

References 48 publications

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“…Execution of apoptosis is associated with a prototypical sequence of morphological events that include nuclear shrinkage, plasma membrane blebbing, chromatin condensation, extrusion of the apoptotic cell, nuclear fragmentation and disaggregation into apoptotic bodies (Saraste and Pulkki 2000). In epithelial cells, the two latter events are usually preceded by extrusion that removes the apoptotic body before fragmentation (Rosenblatt et al 2001;Gagliardi et al 2018). In MCF10A cells, extrusion however was only successful in 40% of apoptotic events, while in 60% of the events, formation of apoptotic bodies was occurring within the monolayer.…”

Section: Erk/akt Waves Are Initiated During the Early Morphological Ementioning

confidence: 99%

“…Next, we explored the functional significance of the apoptosis-triggered ERK/Akt waves. We first tested the hypothesis that ERK/Akt waves regulate the cytoskeletal process of epithelial extrusion, which requires tight coordination of the apoptotic cell and its neighbors (Gagliardi et al 2018;Rosenblatt et al 2001). This hypothesis might be in line with the existence of waves of ERK pulses that regulate myosin contractility to organize collective cell migration (Aoki et al 2017).…”

Section: Erk/akt Waves Do Not Regulate Cell Extrusionmentioning

confidence: 99%

“…2G), we hypothesized that a similar ERK-dependent contractile mechanism might actuate mechanical forces participating in extrusion and/or closing of the epithelial gap. To test this hypothesis, we used a previously established assay (Gagliardi et al 2018) based on the detection of apoptotic debris extruded in the supernatant to evaluate the cumulative effect of extrusion of an epithelial population ( Fig. S5A).…”

Section: Erk/akt Waves Do Not Regulate Cell Extrusionmentioning

confidence: 99%

“…Coordination between epithelial extrusion and cell division is crucial to maintain an adequate cell density (Marinari et al 2012;Gudipaty et al 2017;Eisenhoffer et al 2012). Coordination of apoptotic cells with healthy neighboring cells contributes to epithelial integrity by closing the gaps resulting from the extrusion of dying cells (Gagliardi et al 2018;Gu et al 2011). Apoptosis can control the fate of neighboring cells.…”

Section: Introductionmentioning

confidence: 99%

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Collective ERK/Akt activity waves orchestrate epithelial homeostasis by driving apoptosis-induced survival

Gagliardi

Dobrzyński

Jacques

et al. 2020

Preprint

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Cell death events continuously challenge epithelial barrier function, yet are crucial to eliminate old or critically damaged cells. How such apoptotic events are spatio-temporally organized to maintain epithelial homeostasis remains unclear. We observe waves of Extracellular Signal-Regulated Kinase (ERK) and AKT serine/threonine kinase (Akt) activity pulses that originate from apoptotic cells and propagate radially to healthy surrounding cells. Such a propagation requires Epidermal Growth Factor Receptor (EGFR) and matrix metalloproteinase (MMP) signaling. At the single-cell level, ERK/Akt waves act as spatial survival signals that locally protect cells in the vicinity of the epithelial injury from apoptosis for a period of 3-4 hours. At the cell population level, ERK/Akt waves maintain epithelial homeostasis (EH) in response to mild or intense insults. Disruption of this spatial signaling system results in the inability of a model epithelial tissue to ensure barrier function in response to cellular stress.

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Section: Erk/akt Waves Are Initiated During the Early Morphological Ementioning

confidence: 99%

Section: Erk/akt Waves Do Not Regulate Cell Extrusionmentioning

confidence: 99%

Section: Erk/akt Waves Do Not Regulate Cell Extrusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Collective ERK/Akt activity waves orchestrate epithelial homeostasis by driving apoptosis-induced survival

Gagliardi

Dobrzyński

Jacques

et al. 2020

Preprint

Self Cite

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“…Apical extrusion arose in response to the elevated contractility of the mosaic Snail 6SA cells that surprisingly did not concomitantly involve EMT. Thus, it closely resembles the extrusion response to epithelial apoptosis, where enhanced contractility in the apoptotic cell stimulates its neighbours to drive apical extrusion (Gagliardi, Somale et al 2018) (Michael, Meiring et al 2016). However, the extrusion of Snail 6SA cells was not accompanied by apoptosis, suggesting that the principal stimulus may have been mechanical.…”

Section: Discussionmentioning

confidence: 94%

Snail induces epithelial cell extrusion through transcriptional control of RhoA contractile signaling and cell matrix adhesion

Wee

Zadeh

Verma

et al. 2019

Preprint

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Cell extrusion is a morphogenetic process that is implicated in epithelial homeostasis and highly dependent on the cellular insult and context. Minorities of cells expressing HRasV12 or undergoing apoptosis are typically extruded apically in vertebrate cells. However, basal extrusion (delamination) predominates when mammalian cells express oncogenic KRas and during development in Drosophila. To explore if the morphogenetic transcription factor, Snail, induces extrusion, we inducibly expressed a metabolically stabilized Snail6SA transgene mosaically in confluent MCF-7 monolayers. We found that the morphogenetic impact of Snail6SA was critically influenced by the proportion of cells in which it was expressed. When expressed in small clusters (<3 cells) within confluent monolayers, Snail6SA expression induced apical cell extrusion. In contrast, confluent cultures of Snail6SA expressing cells were retained in the monolayer to eventually undergo basal extrusion (delamination). Transcriptomic profiling revealed that Snail6SA did not substantively alter the balance of epithelial:mesenchymal genes. However, we identified a gene transcriptional network that led to the upregulation of RhoA signalling, actomyosin contractility and reduced basal adhesion in Snail6SA expressing cells. We show that this was necessary to drive both apical extrusion and basal delamination. Thus, contractile upregulation by RhoA along with weakened basal adhesion provides a pathway for Snail to influence epithelial morphogenesis independently of classic Epithelial to Mesenchymal Transition (EMT).

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Myotonic dystrophy kinase‐related CDC42‐binding kinase α, a new transferrin receptor type 2‐binding partner, is a regulator of erythropoiesis

et al. 2021

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Efficient erythropoiesis relies on the expression of the transferrin receptor type 2 (TFR2). In erythroid precursors, TFR2 facilitates the export of the erythropoietin receptor (EPOR) to cell surface, which ensures the survival and proliferation of erythroblasts. Although TFR2 has a crucial role in erythropoiesis regulation, its mechanism of action remains to be clarified. To understand its role better, we aimed at identifying its protein partners by mass‐spectrometry after immunoprecipitation in erythroid cells. Here we report the kinase MRCKα (myotonic dystrophy kinase‐related CDC42‐binding kinase α) as a new partner of both TFR2 and EPOR in erythroblasts. We show that MRCKα is co‐expressed with TFR2, and TFR1 during terminal differentiation and regulates the internalization of the two types of transferrin receptors. The knockdown of MRCKα by shRNA in human primary erythroblasts leads to a decreased cell surface expression of both TFR1 and TFR2, an increased cell‐surface expression of EPOR, and a delayed differentiation. Additionally, knockout of Mrckα in the murine MEDEP cells also leads to a striking delay in erythropoiesis, showcasing the importance of this kinase in both species. Our data highlight the importance of MRCKα in the regulation of erythropoiesis.

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MRCKα is activated by caspase cleavage to assemble an apical actin ring for epithelial cell extrusion

Cited by 32 publications

References 48 publications

Collective ERK/Akt activity waves orchestrate epithelial homeostasis by driving apoptosis-induced survival

Collective ERK/Akt activity waves orchestrate epithelial homeostasis by driving apoptosis-induced survival

Snail induces epithelial cell extrusion through transcriptional control of RhoA contractile signaling and cell matrix adhesion

Myotonic dystrophy kinase‐related CDC42‐binding kinase α, a new transferrin receptor type 2‐binding partner, is a regulator of erythropoiesis

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