Article

Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 05/2011; 193(4):667-76. DOI: 10.1083/jcb.201010075
Source: PubMed

ABSTRACT

To maintain an intact barrier, epithelia eliminate dying cells by extrusion. During extrusion, a cell destined for apoptosis signals its neighboring cells to form and contract a ring of actin and myosin, which squeezes the dying cell out of the epithelium. Here, we demonstrate that the signal produced by dying cells to initiate this process is sphingosine-1-phosphate (S1P). Decreasing S1P synthesis by inhibiting sphingosine kinase activity or by blocking extracellular S1P access to its receptor prevented apoptotic cell extrusion. Extracellular S1P activates extrusion by binding the S1P(2) receptor in the cells neighboring a dying cell, as S1P(2) knockdown in these cells or its loss in a zebrafish mutant disrupted cell extrusion. Because live cells can also be extruded, we predict that this S1P pathway may also be important for driving delamination of stem cells during differentiation or invasion of cancer cells.

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    • "S1P expressed by apoptotic cells or RasV12-transformed cells has been reported to be an important regulator for the elimination of those cells from the epithelium (Gu et al., 2011; Slattum et al., 2014). SphKI2 is a specific inhibitor for sphingosine kinase 1 (SphK1) that catalyzes the production of S1P from sphingosine. "
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    ABSTRACT: At the initial step of carcinogenesis, transformation occurs in single cells within epithelia where the newly emerging transformed cells are surrounded by normal epithelial cells. A recent study has revealed that normal epithelial cells have an ability to sense and actively eliminate the neighboring transformed cells, a process named EDAC (Epithelial Defense Against Cancer). However, the molecular mechanism of this tumor-suppressive activity remains largely unknown. In this study, we have investigated a role for the sphingosine-1-phosphate (S1P)-S1P receptor 2 (S1PR2) pathway in EDAC. First, we show that addition of the S1PR2 inhibitor significantly suppresses apical extrusion of RasV12-transformed cells that are surrounded by normal cells. In addition, knockdown of S1PR2 in normal cells induces the same effect, indicating that S1PR2 in the surrounding normal cells plays a positive role in the apical elimination of the transformed cells. Importantly, not endogenous S1P but exogenous S1P is involved in this process. By using FRET analyses, we demonstrate that S1PR2 mediates Rho activation in normal cells neighboring RasV12-transformed cells, thereby promoting accumulation of filamin, a crucial regulator of EDAC. Collectively, these data indicate that S1P is a key extrinsic factor that affects the outcome of cell competition between normal and transformed epithelial cells.
    Preview · Article · Dec 2015 · Molecular biology of the cell
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    • "Furthermore , other processes causative to extrusion , such as sphingosine - 1 - phosphate ( S1P ) production , could make CDC42V12 - driven apical extrusion more efficient than extrusion elicited by Cle - cad and TEVp ( Gu et al . , 2011 ) . Furthermore , the relative requirements for MEK – ERK signalling in TEVp - treated Cle - cadHA - expressing extruding cells and CDC42V12 - expressing extruding cells have not been studied ."
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    ABSTRACT: Epithelial cell extrusion and subsequent apoptosis is a key mechanism to prevent accumulation of excess cells. Conversely, when driven by oncogene expression, apical cell extrusion is followed by proliferation and represents an initial step of tumorigenesis. E-cadherin (E-cad), the main component of adherens junctions, has been shown to be essential for epithelial cell extrusion, but its mechanistic contribution remains unclear. Here, we provide clear evidence that cell extrusion can be driven by E-cad cleavage, both in a wild type and oncogenic environment. We first show that CDC42 activation in a single epithelial cell results in its efficient MMP-sensitive extrusion through MEK signaling activation and is supported by E-cad cleavage. Second, using an engineered cleavable form of E-cad, we demonstrate that sole extracellular E-cad truncation at the plasma membrane promotes apical extrusion. We propose that extracellular cleavage of E-cad generates a rapid change in cell-cell adhesion sufficient to drive apical cell extrusion. Whereas in normal epithelia, extrusion is followed by apoptosis, when combined to active oncogenic signaling, it is coupled to cell proliferation.
    Full-text · Article · Jun 2014 · Journal of Cell Science
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    • "Following identification of S1PR2 and NF-κB as important mediators of S1P induced IL-8 release, the question of how this receptor signals to the transcription factor arises. Others have described the effect of S1PR2 blockade on various physiological processes; for example antagonizing S1PR2 in human bronchial epithelial cells inhibits the extrusion of apoptotic cells [21]. S1P receptor G protein coupling is complex, with S1PR2 coupling to a variety of Gα subunits including Gαs, Gαi, Gα12/13, Gαq and G0 [22]. "
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    ABSTRACT: The airway epithelium may release pro-inflammatory cytokines and chemokines in the asthmatic airway. Sphingosine 1-phosphate (S1P) is a bioactive lipid, increased in the airways of asthmatics, that may trigger the release of the potent neutrophil chemoattractant Interleukin-8 (IL-8) by epithelial cells. S1P is a ligand for 5 G protein-coupled receptors, S1PR1-5. We wished to explore the mechanisms of S1P induced IL-8 secretion with regard to the receptor(s) and downstream signaling events involved. Our results indicate that S1P induced IL-8 release is mediated by S1PR2 and the transcription factor NF-κB. Since the Epidermal Growth Factor Receptor (EGFR) and reactive oxygen species (ROS) have been implicated in IL-8 release in response to activation of other G protein-coupled receptors, we examined their importance in S1P induced IL-8 release and established that they are not involved. This study reveals S1PR2 and NF-κB as potential therapeutic targets in neutrophilic airway diseases such as severe asthma.
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