An apical MRCK-driven morphogenetic pathway controls epithelial polarity

Zihni, Ceniz; Vlassaks, Evi; Terry, Stephen J.; Carlton, Jeremy G.; Leung, Thomas; Olson, Michael F.; Pichaud, Franck; Balda, María S.; Matter, Karl

doi:10.1038/ncb3592

Cited by 66 publications

(93 citation statements)

References 52 publications

(93 reference statements)

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“…8A) and may contribute to regulating its directionality. Recent findings on apical domain expansion in epithelial cells shed light on how this process could be involved in extrusion 57,66 . Dbl3 is a regulatory GEF of Cdc42, which has been shown to be necessary for oncogenic extusion 7 .…”

Section: Discussionmentioning

confidence: 99%

Src-transformed cells hijack mitosis to extrude from the epithelium

Anton

Kajita

Narumi

et al. 2018

Preprint

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At the initial stage of carcinogenesis single mutated cells appear within an epithelium. Mammalian in vitro experiments show that potentially cancerous cells undergo live apical extrusion from normal monolayers. However, the mechanism underlying this process in vivo remains poorly understood. Mosaic expression of the oncogene vSrc in a simple epithelium of the early zebrafish embryo results in apical extrusion of transformed cells. Here we find that during extrusion components of the cytokinetic ring are recruited to adherens junctions of transformed cells, stimulating formation of a misoriented pseudo cytokinetic ring. During extrusion, the ring constricts and separates the basal from the apical part of the cell releasing both from the epithelium. This process requires cell cycle progression and occurs immediately after vSrc-transformed cell enters mitosis. To achieve extrusion, vSrc coordinates cell cycle progression, junctional integrity, cell survival and apicobasal polarity. Without vSrc, modulating these cellular processes reconstitutes vSrc-like extrusion, confirming their sufficiency for this process.

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Section: Discussionmentioning

confidence: 99%

Src-transformed cells hijack mitosis to extrude from the epithelium

Anton

Kajita

Narumi

et al. 2018

Preprint

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“…Our data are especially intriguing given the known role of Baz as a regulator of apicomedial actomyosin contractility in the Drosophila amnioserosa, where it regulates pulsatile contractions and the degree of coupling to cell shape change, via effects on atypical protein kinase C (aPKC; David et al, 2010;Durney et al, 2018). Experiments in mammalian cells suggest Par3 may help regulate how cells balance apicomedial versus junctional contractility (Zihni et al, 2017). Par3 and ZO-1 are in proximity in mammalian cells (e.g.…”

Section: Cno: More Than Just a Junction:cytoskeletal Linkermentioning

confidence: 98%

The Drosophila Afadin and ZO-1 homologs Canoe and Polychaetoid act in parallel to maintain epithelial integrity when challenged by adherens junction remodeling

Manning

Perez-Vale

Schaefer

et al. 2019

Preprint

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During morphogenesis cells must change shape and move without disrupting tissue integrity. This requires cell-cell junctions to allow dynamic remodeling while resisting force generated by the actomyosin cytoskeleton. Multiple proteins play roles in junctional-cytoskeletal linkage, but the mechanisms by which they act remain unclear. Drosophila Canoe maintains adherens junction-cytoskeletal linkage during gastrulation.Canoe's mammalian homolog Afadin plays similar roles in cultured cells, working in parallel with ZO-1 proteins, particularly at multicellular junctions. We took these insights back into the fly embryo, exploring how cells maintain epithelial integrity when challenged by adherens junction remodeling during germband extension and dorsal closure. We found Canoe helps cells maintain junctional-cytoskeletal linkage when challenged by the junctional remodeling inherent in mitosis, cell intercalation and neuroblast invagination, or by forces generated by the actomyosin cable at the leading edge. However, even in the absence of Canoe many cells retain epithelial integrity. This is explained by a parallel role played by the ZO-1 homolog Polychaetoid. In embryos lacking both Canoe and Polychaetoid, cell junctions fail early, with multicellular junctions especially sensitive, leading to widespread loss of epithelial integrity. Our data suggest Canoe and Polychaetoid stabilize Bazooka/Par3 at cell-cell junctions, helping maintain balanced apical contractility and tissue integrity.

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“…The polarity defects may also provide an explanation for why low expression levels of myosin-18B are linked to carcinoma progression [20, 26, 27]. Contractile actomyosin bundles contribute to proper polarity of epithelial cells [38, 39], and thus the lack of functional actomyosin bundles in epithelial cancers is expected to enhance the epithelial- mesenchymal transition (EMT) of carcinoma cells.…”

Section: Disscussionmentioning

confidence: 99%

Myosin-18B Promotes the Assembly of Myosin II Stacks for Maturation of Contractile Actomyosin Bundles

et al. 2019

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SUMMARY Cell adhesion, morphogenesis, mechanosensing, and muscle contraction rely on contractile actomyosin bundles, where the force is produced through sliding of bipolar myosin II filaments along actin filaments. The assembly of contractile actomyosin bundles involves registered alignment of myosin II filaments and their subsequent fusion into large stacks. However, mechanisms underlying the assembly of myosin II stacks, and their physiological functions have remained elusive. Here we identified myosin-18B, an unconventional myosin, as a stable component of contractile stress fibers. Myosin-18B co-localized with myosin II motor domains in stress fibers, and was enriched at the ends of myosin II stacks. Importantly, myosin-18B deletion resulted in drastic defects in the concatenation and persistent association of myosin II filaments with each other, and thus led to severely impaired assembly of myosin II stacks. Consequently, lack of myosin-18B resulted in defective maturation of actomyosin bundles from their precursors in osteosarcoma cells. Moreover, myosin-18B knockout cells displayed abnormal morphogenesis, migration, and ability to exert forces to the environment. These results reveal a critical role for myosin-18B in myosin II stack assembly, and provide evidence that myosin II stacks are important for a variety of vital processes in cells.

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An apical MRCK-driven morphogenetic pathway controls epithelial polarity

Cited by 66 publications

References 52 publications

Src-transformed cells hijack mitosis to extrude from the epithelium

Src-transformed cells hijack mitosis to extrude from the epithelium

The Drosophila Afadin and ZO-1 homologs Canoe and Polychaetoid act in parallel to maintain epithelial integrity when challenged by adherens junction remodeling

Myosin-18B Promotes the Assembly of Myosin II Stacks for Maturation of Contractile Actomyosin Bundles

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