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Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase

The type II transmembrane serine protease Matriptase 1 (ST14) is commonly known as an oncogene, yet it also plays an understudied role in suppressing carcinogenesis. This double face is evident in the embryonic epidermis of zebrafish loss-of-function mutants in the cognate Matriptase inhibitor Hai1a...

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Autores principales: Armistead, Joy, Hatzold, Julia, van Roye, Anna, Fahle, Evelin, Hammerschmidt, Matthias
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041680/
https://www.ncbi.nlm.nih.gov/pubmed/31819976
http://dx.doi.org/10.1083/jcb.201905190
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author Armistead, Joy
Hatzold, Julia
van Roye, Anna
Fahle, Evelin
Hammerschmidt, Matthias
author_facet Armistead, Joy
Hatzold, Julia
van Roye, Anna
Fahle, Evelin
Hammerschmidt, Matthias
author_sort Armistead, Joy
collection PubMed
description The type II transmembrane serine protease Matriptase 1 (ST14) is commonly known as an oncogene, yet it also plays an understudied role in suppressing carcinogenesis. This double face is evident in the embryonic epidermis of zebrafish loss-of-function mutants in the cognate Matriptase inhibitor Hai1a (Spint1a). Mutant embryos display epidermal hyperplasia, but also apical cell extrusions, during which extruding outer keratinocytes carry out an entosis-like engulfment and entrainment of underlying basal cells, constituting a tumor-suppressive effect. These counteracting Matriptase effects depend on EGFR and the newly identified mediator phospholipase D (PLD), which promotes both mTORC1-dependent cell proliferation and sphingosine-1-phosphate (S1P)–dependent entosis and apical cell extrusion. Accordingly, hypomorphic hai1a mutants heal spontaneously, while otherwise lethal hai1a amorphs are efficiently rescued upon cotreatment with PLD inhibitors and S1P. Together, our data elucidate the mechanisms underlying the double face of Matriptase function in vivo and reveal the potential use of combinatorial carcinoma treatments when such double-face mechanisms are involved.
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spelling pubmed-70416802020-08-03 Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase Armistead, Joy Hatzold, Julia van Roye, Anna Fahle, Evelin Hammerschmidt, Matthias J Cell Biol Research Articles The type II transmembrane serine protease Matriptase 1 (ST14) is commonly known as an oncogene, yet it also plays an understudied role in suppressing carcinogenesis. This double face is evident in the embryonic epidermis of zebrafish loss-of-function mutants in the cognate Matriptase inhibitor Hai1a (Spint1a). Mutant embryos display epidermal hyperplasia, but also apical cell extrusions, during which extruding outer keratinocytes carry out an entosis-like engulfment and entrainment of underlying basal cells, constituting a tumor-suppressive effect. These counteracting Matriptase effects depend on EGFR and the newly identified mediator phospholipase D (PLD), which promotes both mTORC1-dependent cell proliferation and sphingosine-1-phosphate (S1P)–dependent entosis and apical cell extrusion. Accordingly, hypomorphic hai1a mutants heal spontaneously, while otherwise lethal hai1a amorphs are efficiently rescued upon cotreatment with PLD inhibitors and S1P. Together, our data elucidate the mechanisms underlying the double face of Matriptase function in vivo and reveal the potential use of combinatorial carcinoma treatments when such double-face mechanisms are involved. Rockefeller University Press 2019-12-09 /pmc/articles/PMC7041680/ /pubmed/31819976 http://dx.doi.org/10.1083/jcb.201905190 Text en © 2019 Armistead et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Armistead, Joy
Hatzold, Julia
van Roye, Anna
Fahle, Evelin
Hammerschmidt, Matthias
Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase
title Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase
title_full Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase
title_fullStr Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase
title_full_unstemmed Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase
title_short Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase
title_sort entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of matriptase
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041680/
https://www.ncbi.nlm.nih.gov/pubmed/31819976
http://dx.doi.org/10.1083/jcb.201905190
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