E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo

Wang, Xue; Dong, Baijun; Zhang, Kai; Ji, Zhongzhong; Cheng, Chung–Ying; Zhao, Huifang; Sheng, Yaru; Li, Xiaoxia; Fan, Liancheng; Xue, Wei; Gao, Wei‐Qiang; Zhu, Helen He

doi:10.1371/journal.pgen.1007609

Cited by 52 publications

(47 citation statements)

References 44 publications

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“…To produce rapidly cycling and highly proliferative transient amplifying cells, the quiescent stem cells in the epidermal basal layer may undergo asymmetric division (Hsu et al, 2014;Kretzschmar and Watt, 2014). Previous studies have shown that depletion of E-cadherin expression in cells disturbs spindle orientation and cellular polarity during cell division (Wang et al, 2018). In the present study, downregulation of E-cadherin expression was determined in Wwox −/− mouse epidermal keratinocytes.…”

Section: Discussionmentioning

confidence: 74%

Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Chou

Lai

Chang

et al. 2020

Front. Cell Dev. Biol.

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Deficiency of tumor suppressor WW domain-containing oxidoreductase (WWOX) in humans and animals leads to growth retardation and premature death during postnatal developmental stages. Skin integrity is essential for organism survival due to its protection against dehydration and hypothermia. Our previous report demonstrated that human epidermal suprabasal cells express WWOX protein, and the expression is gradually increased toward the superficial differentiated cells prior to cornification. Here, we investigated whether abnormal skin development and homeostasis occur under Wwox deficiency that may correlate with early death. We determined that keratinocyte proliferation and differentiation were decreased, while apoptosis was increased in Wwox −/− mouse epidermis and primary keratinocyte cultures and WWOX-knockdown human HaCaT cells. Without WWOX, progenitor cells in hair follicle junctional zone underwent massive proliferation in early postnatal developmental stages and the stem/progenitor cell pools were depleted at postnatal day 21. These events lead to significantly decreased epidermal thickness, dehydration state, and delayed hair development in Wwox −/− mouse skin, which is associated with downregulation of prosurvival MEK/ERK signaling in Wwox −/− keratinocytes. Moreover, Wwox depletion results in substantial downregulation of dermal collagen contents in mice. Notably, Wwox −/− mice exhibit severe loss of subcutaneous adipose tissue and significant hypothermia. Collectively, our knockout mouse model supports the validity of WWOX in assisting epidermal and adipose homeostasis, and the involvement of prosurvival ERK pathway in the homeostatic responses regulated by WWOX.

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Section: Discussionmentioning

confidence: 74%

Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Chou

Lai

Chang

et al. 2020

Front. Cell Dev. Biol.

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“…In line with this, Scribble was recently shown to exist as part of a ternary complex with Ecad and LGN, a known determinant for directing spindle orientation. Knockdown of either Ecad or Scribble was sufficient to attenuate their reciprocal interactions with LGN (Wang et al, 2018).…”

Section: Polarizing Mitosis: Roles For Scribble In Asymmetric Cell DImentioning

confidence: 99%

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

Bonello

Peifer

2018

Journal of Cell Biology

114

110

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Key events ranging from cell polarity to proliferation regulation to neuronal signaling rely on the assembly of multiprotein adhesion or signaling complexes at particular subcellular sites. Multidomain scaffolding proteins nucleate assembly and direct localization of these complexes, and the protein Scribble and its relatives in the LAP protein family provide a paradigm for this. Scribble was originally identified because of its role in apical–basal polarity and epithelial integrity in Drosophila melanogaster. It is now clear that Scribble acts to assemble and position diverse multiprotein complexes in processes ranging from planar polarity to adhesion to oriented cell division to synaptogenesis. Here, we explore what we have learned about the mechanisms of action of Scribble in the context of its multiple known interacting partners and discuss how this knowledge opens new questions about the full range of Scribble protein partners and their structural and signaling roles.

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“…Dlg1 has been implicated in LGN localisation in neuroepithelial cells; we saw a significant decrease in the membrane to cytoplasmic ratio of LGN in Dlg1 depleted cells ( Figure 4a and 4b). In some cells, however, LGN localisation depends on laterally-localised E-Cadherin [24], and E-Cadherin is required for correct spindle orientation in mouse prostate epithelial cells [25]. To test whether Dlg1 acts through localisation of E-Cadherin, we stained MDCKII cells for E-Cadherin following both CASK and Dlg1 knockdown.…”

Section: The Cask-dlg1 Interaction Is Required For Localisation Of Thmentioning

confidence: 99%

“…Importantly we show that both CASK and Dlg1 are required for spindle orientation and lumen formation. This requirement for Dlg1 may explain in part the multilumen phenotype seen in SHIP2-depleted MDCKII cells which also mislocalise Dlg1 [32], as well as in prostate epithelial depleted of E-Cadherin where Dlg1 is lost from the membrane due to disruption of adherens junctions [25].…”

Section: The Cask-dlg1 Interaction Is Required For Localisation Of Thmentioning

confidence: 99%

The interaction between the tumour suppressor Dlg1 and the MAGUK protein CASK is required for oriented cell division in mammalian epithelia

Porter

White

Mack

et al. 2018

Preprint

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Oriented cell divisions are important for the formation of normal epithelial structures. Dlg1, a tumour suppressor, is required for oriented cell division in Drosophila epithelia and chick neuroepithelia, but how Dlg1 is localised to the membrane and its importance in mammalian epithelia are unknown. Here we show that Dlg1 is required in non-transformed mammalian epithelial cells for oriented cell divisions, and for normal lumen formation in 3D culture. We demonstrate that CASK, a membrane-associated scaffold, is the factor responsible for Dlg1 membrane localisation during spindle orientation, and thereby identify a new cellular function for CASK. We show that depletion of CASK leads to misoriented divisions in 3D, and to the formation of multilumen structures in cultured kidney and breast epithelial cells. Blocking the direct interaction between CASK and Dlg1 with an interfering peptide disrupts spindle orientation and causes multilumen formation. We further show that the Dlg1-CASK interaction is important for the membrane localisation of the canonical LGN-NuMA complex, required for attachment of the mitotic spindle to the membrane and its correct positioning, as well as for astral microtubule stability. Together these results establish the importance of the CASK-Dlg1 interaction in oriented cell division and epithelial integrity.

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E-cadherin bridges cell polarity and spindle orientation to ensure prostate epithelial integrity and prevent carcinogenesis in vivo

Cited by 52 publications

References 44 publications

Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Wwox Deficiency Causes Downregulation of Prosurvival ERK Signaling and Abnormal Homeostatic Responses in Mouse Skin

Scribble: A master scaffold in polarity, adhesion, synaptogenesis, and proliferation

The interaction between the tumour suppressor Dlg1 and the MAGUK protein CASK is required for oriented cell division in mammalian epithelia

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