Plectin is a novel regulator for apical extrusion of RasV12-transformed cells

Kadeer, Ailijiang; Maruyama, Takeshi; Kajita, Mihoko; Morita, Tomoko; Sasaki, Ayana; Ohoka, Atsuko; Ishikawa, Susumu; Ikegawa, Masaya; Shimada, Takashi; Fujita, Yasuyuki

doi:10.1038/srep44328

Cited by 35 publications

(39 citation statements)

References 30 publications

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“…The close proximity of DJs, associated intermediate filaments, and the actomyosin cable may mechanically link the actomyosin cable and desmosomes, either with or without cytoskeletal cross-linkers [12, 34]. A recent study reported a physical coupling between desmoglein 1 and actin via cortactin during skin differentiation, which in turn increases junctional tension in the tissue [12].…”

Section: Resultsmentioning

confidence: 99%

Desmosomal coupling in apoptotic cell extrusion

Thomas¹,

Ladoux

Toyama

2019

Preprint

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The mechanical coupling of epithelia enables coordination of tissue functions and collective tissue movements during different developmental and physiological processes. This coupling is ensured by cell-cell junctions, including adherens junctions (AJs) and desmosomal junctions (DJs) [1, 2]. During apoptosis, or programmed cell death, a dead cell is expelled from the tissue by coordinated processes between the dying cell and its neighbors. Apoptotic cell extrusion is driven by actomyosin cable formation and its contraction, and lamellipodial crawling of the neighboring cells ( Fig. S1A-A'', Movie S1) [3][4][5][6]. Throughout cell extrusion, the mechanical coupling of epithelia needs to be maintained in order to preserve tissue homeostasis [3]. Although much is known about the regulation of AJs in apoptotic cell extrusion [6][7][8][9], the role and dynamics of DJs during this process remains poorly understood.Here, we show that DJs stay intact throughout and are crucial for apoptotic cell extrusion.Pre-existing DJs between the apoptotic cell and neighboring non-dying cells remain intact even during the formation of de novo DJs between non-dying cells, suggesting that the neighboring cells possess two DJs in the middle of apoptotic cell extrusion. We further found that an actomyosin cable formed in the vicinity of DJs upon apoptosis, and subsequently deviated from DJs during its constriction. Interestingly, the departure of the actomyosin cable from DJs coincided with the timing when DJs lost their straightness, suggesting a release of junctional tension at DJs, and a mechanical coupling between DJs and actomyosin contractility. The depletion of desmoplakin, which links desmosomes and intermediate filaments, resulted in defective apical contraction and an inability to form de novo DJs, leading to a failure of apoptotic cell extrusion. Our study provides a framework to explain how desmosomes play pivotal roles in maintaining epithelial sheet integrity during apoptotic cell extrusion. 3 RESULTS AND DISCUSSIONDuring apoptotic cell extrusion, adherens junction components including E-cadherin and α and β -catenins display a reduction in their levels at the interface between the apoptotic cell and neighboring cells. This reduction coincides with membrane disengagement, actomyosin cable formation, and relaxation of tissue tension [6]. Here, we investigate the dynamics of desmosomal junctions (DJs), which are a part of the tripartite epithelial junctions known to influence dynamic processes such as collective cell migration [10] and skin differentiation [11, 12], during cell extrusion. Desmosomal junctions stay intact throughout apoptotic cell extrusionTo understand how DJs were remodeled during the course of apoptotic cell extrusion, we used a UV laser to induce DNA damage and subsequent apoptotic cell extrusion (Supplemental experimental procedures, [5]), and followed the progression of extrusion using confocal microscopy ( Fig. 1A). We first examined the distribution of desmoglein, one of the two cadherin types found in...

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Section: Resultsmentioning

confidence: 99%

Desmosomal coupling in apoptotic cell extrusion

Thomas¹,

Ladoux

Toyama

2019

Preprint

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“…Cytoskeleton reorganization is a fundamental process for the apical extrusion of apoptotic epithelial cells and for cell migration/invasion of metastatic cells 33 - 35 . Prior to extrusion, cells present an overall increase in F-actin levels and a change in actomyosin localization, from basal to apico-cortical deposition 36 .…”

Section: Resultsmentioning

confidence: 99%

“…Fish were maintained at a water temperature of 28 °C. The following fish were used: wild-type AB strain; Et(−26.5Hsa.WT1-gata2:EGFP) cn1 (epi:GFP) 14 ; Tg(myl7:mRFP) 90 , Tg(hsp70l:bmp2b) fr13 and Tg( hsp70l::noggin3 ) fr14 45 , Tg( kdrl::mCherry ) ci5 (from Elke Obeŕs laboratory), Tg( uas::myc-Notch1a-intra ) kca3 , Tg( hsp70l::Gal4 ) kca4 91 ; Tg( fli1a:gal4 ) ubs 3 Tg 55 , Tg( βactin:LifeActin:RFP ) e 2212 Tg 92 , Tg( actb2:myl12.1-mCherry ) e 1954 93 , Tg( BRE-AAVmlp:dmKO2 ) mw 40 46 , Et( krt4:EGFP ) sqet 33 mi 60 A 57 , Tg( Tp1:CreERT2 ) s951 60 , Tg (- 3.5ubb:LOXP-EGFP-LOXP-mCherry ) cz1702 94 Tg(fli1a:eGFP ) 61 and Tg( UAS:mRFP ) 95 .…”

Section: Methodsmentioning

confidence: 99%

Actomyosin dynamics, Bmp and Notch signaling pathways drive apical extrusion of proepicardial cells

Mercader

2018

Preprint

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The epicardium, the outer mesothelial layer enclosing the myocardium, plays key roles in heart development and regeneration. During embryogenesis it arises from the proepicardium (PE), a cell cluster that appears in the dorsal pericardium close to the venous pole of the heart. Little is known about how the PE emerges from the pericardial mesothelium. Using the zebrafish model and a combination of genetic tools, pharmacological agents and quantitative in vivo imaging we reveal that a coordinated collective movement of the dorsal pericardium drives PE formation. We found that PE cells are apically extruded in response to actomyosin activity. Our results reveal that the coordinated action of Notch/Bmp pathways is critically needed for apical extrusion of PE cells. More generally, by comparison to cell extrusion for the elimination of unfit cells from epithelia, our results describe a unique mechanism where extruded cell viability is maintained.

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“…Previous studies have shown that the paxillin‐plectin‐EPLIN complex is accumulated in RasV12‐ or Src‐transformed cells when they are surrounded by normal epithelial cells, which promote apical elimination of the transformed cells (Kadeer et al, ; Kasai et al, ; Ohoka et al, ). But, knock‐down of EPLIN does not significantly influence accumulation of NMHC‐IIA, and knock‐down of NMHC‐IIA does not affect accumulation of EPLIN (Supporting Information Figure S4a–e).…”

Section: Discussionmentioning

confidence: 99%

Accumulation of the myosin‐II‐spectrin complex plays a positive role in apical extrusion of Src‐transformed epithelial cells

et al. 2018

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At the initial stage of carcinogenesis, transformation occurs in single cells within the epithelium. Recent studies have revealed that the newly emerging transformed cells are often apically eliminated from epithelial tissues. However, the underlying molecular mechanisms of this cancer preventive phenomenon still remain elusive. In this study, we first demonstrate that myosin-II accumulates in Src-transformed cells when they are surrounded by normal epithelial cells. Knock-down of the heavy chains of myosin-II substantially diminishes apical extrusion of Src cells, suggesting that accumulated myosin-II positively regulates the apical elimination of transformed cells. Furthermore, we have identified β-spectrin as a myosin-II-binding protein under the coculture of normal and Src-transformed epithelial cells. β-spectrin is also accumulated in Src cells that are surrounded by normal cells, and the β-spectrin accumulation is regulated by myosin-II. Moreover, knock-down of β-spectrin significantly suppresses apical extrusion of Src cells. Collectively, these results indicate that accumulation of the myosin-II-spectrin complex plays a positive role in apical extrusion of Src-transformed epithelial cells. Further elucidation of the molecular mechanisms of apical extrusion would lead to the establishment of a novel type of cancer preventive medicine.

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Plectin is a novel regulator for apical extrusion of RasV12-transformed cells

Cited by 35 publications

References 30 publications

Desmosomal coupling in apoptotic cell extrusion

Desmosomal coupling in apoptotic cell extrusion

Actomyosin dynamics, Bmp and Notch signaling pathways drive apical extrusion of proepicardial cells

Accumulation of the myosin‐II‐spectrin complex plays a positive role in apical extrusion of Src‐transformed epithelial cells

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