c-Jun N-terminal kinase activity supports multiple phases of 3D-mammary epithelial acinus formation

McNally, Sara; McArdle, Emmett; Gilligan, Emer; Napoletano, Silvia; Gajewska, Małgorzata; Bergin, Orla; McCarthy, Sarah; Whyte, Jacqueline; Bianchi, Alessandro; Stack, Julianne; Martin, Finian

doi:10.1387/ijdb.113374sm

Cited by 9 publications

(5 citation statements)

References 40 publications

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“…More recently, studies using the drug SP600125, that inhibits JNK and many other protein kinases (Bain et al 2003), indicated that JNK may be required for acinar formation and luminal clearance by human MCF10A mammary epithelial cells (McNally et al 2011). This observation suggested that JNK may play a role in anoikis.…”

Section: Discussionmentioning

confidence: 99%

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JNK Promotes Epithelial Cell Anoikis by Transcriptional and Post-translational Regulation of BH3-Only Proteins

Girnius

Davis

2017

Cell Reports

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Summary Developmental morphogenesis, tissue injury, and oncogenic transformation can cause the detachment of epithelial cells. These cells are eliminated by a specialized form of apoptosis (anoikis). While the processes that contribute to this form of cell death have been studied, the underlying mechanisms remain unclear. Here we tested the role of the cJUN NH2-terminal kinase (JNK) signaling pathway using murine models with compound JNK-deficiency in mammary and kidney epithelial cells. These studies demonstrated that JNK is required for efficient anoikis in vitro and in vivo. Moreover, JNK-promoted anoikis required pro-apoptotic members of the BCL2 family of proteins. We show that JNK acts through a BAK/BAX-dependent apoptotic pathway by increasing BIM expression and phosphorylating BMF leading to death of detached epithelial cells.

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Section: Discussionmentioning

confidence: 99%

“…This controversy has yet to be resolved. More recent studies suggest that JNK may promote epithelial cell anoikis in vitro (McNally et al 2011) and in vivo (Cellurale et al 2012). …”

Section: Introductionmentioning

confidence: 99%

JNK Promotes Epithelial Cell Anoikis by Transcriptional and Post-translational Regulation of BH3-Only Proteins

Girnius

Davis

2017

Cell Reports

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“…First, anoikis and cell polarity in threedimensional MCF10a acinar cultures both depend on JNK signaling (McNally et al, 2011). Second, the mammary-glandspecific knockout of JNK1 and JNK2 (MAPK8 and MAPK9, respectively) demonstrates that they have tumor-suppressive activities that are accompanied by defective luminal clearing, a sign of defective anoikis (Cellurale et al, 2010).…”

Section: Journal Of Cell Sciencementioning

confidence: 99%

Mechanisms that link the oncogenic epithelial–mesenchymal transition to suppression of anoikis

Frisch

Schaller

Cieply

2013

Journal of Cell Science

251

217

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SummaryThe oncogenic epithelial-mesenchymal transition (EMT) contributes to tumor progression in various context-dependent ways, including increased metastatic potential, expansion of cancer stem cell subpopulations, chemo-resistance and disease recurrence. One of the hallmarks of EMT is resistance of tumor cells to anoikis. This resistance contributes to metastasis and is a defining property not only of EMT but also of cancer stem cells. Here, we review the mechanistic coupling between EMT and resistance to anoikis. The discussion focuses on several key aspects. First, we provide an update on new pathways that lead from the loss of E-cadherin to anoikis resistance. We then discuss the relevance of transcription factors that are crucial in wound healing in the context of oncogenic EMT. Next, we explore the consequences of the breakdown of cell-polarity complexes upon anoikis sensitivity, through the Hippo, Wnt and transforming growth factor b (TGF-b) pathways, emphasizing points of crossregulation. Finally, we summarize the direct regulation of cell survival genes through EMT-inducing transcription factors, and the roles of the tyrosine kinases focal adhesion kinase (FAK) and TrkB neurotrophin receptor in EMT-related regulation of anoikis. Emerging from these studies are unifying principles that will lead to improvements in cancer therapy by reprogramming sensitivity of anoikis.

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“…JNK1 and 2 have been reported to be involved in the physiological function of epithelial sheets, for example JNK inhibitors and knockdown of JNK1 block acinus formation, and impair cell polarization and lumen clearance in primary murine mammary epithelial cells (McNally et al . ). In addition, the transepithelial electrical resistance (TER), which can serve as an index of barrier function in epithelial sheets, is associated with JNK activity.…”

Section: Discussionmentioning

confidence: 97%

“…As McNally et al . () demonstrated in primary murine mammary epithelial cells, inactivation of JNK might lead to reduced expression of occludin by inhibiting the binding of transcription factors to its promoter. Thus, multiple factors regulating the localization of tTJs proteins might be affected by changes in the activity of JNK1 or 2 at multiple levels.…”

Section: Discussionmentioning

confidence: 97%

JNK1/2‐dependent phosphorylation of angulin‐1/LSR is required for the exclusive localization of angulin‐1/LSR and tricellulin at tricellular contacts in EpH4 epithelial sheet

et al. 2014

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Tricellular tight junctions (tTJs) are specialized structural variants of tight junctions within tricellular contacts of an epithelial sheet and comprise several transmembrane proteins including lipolysis-stimulated lipoprotein receptor (angulin-1/LSR) and tricellulin. To elucidate the mechanism of its formation, we carried out stepwise screening of kinase inhibitors followed by RNAi screening to identify kinases that regulate intracellular localization of angulin-1/LSR to the tTJs using a fluorescence image-based screen. We found that the activity of JNK1 and JNK2, but not JNK3, was required for the exclusive localization of angulin-1/ LSR at the tTJs. Based on a bioinformatics approach, we estimated the potential phosphorylation site of angulin-1/LSR by JNK1 to be serine 288 and experimentally confirmed that JNK1 directly phosphorylates angulin-1/LSR at this site. We found that JNK2 was also involved in the phosphorylation of angulin-1/LSR. Furthermore, GFP-tagged angulin-1/LSR(S288A), in which serine 288 was substituted by alanine, was observed to be dispersed to bicellular junctions, indicating that phosphorylation of Ser288 is crucial for the exclusive localization of angulin-1/LSR and tricellulin at tTJs. Our fluorescence image-based screening for kinases inhibitor or siRNAs combined with the phosphorylation site prediction could become a versatile and useful tool to elucidate the mechanisms underlying the maintenance of tTJs regulated by kinase networks.

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c-Jun N-terminal kinase activity supports multiple phases of 3D-mammary epithelial acinus formation

Cited by 9 publications

References 40 publications

JNK Promotes Epithelial Cell Anoikis by Transcriptional and Post-translational Regulation of BH3-Only Proteins

JNK Promotes Epithelial Cell Anoikis by Transcriptional and Post-translational Regulation of BH3-Only Proteins

Mechanisms that link the oncogenic epithelial–mesenchymal transition to suppression of anoikis

JNK1/2‐dependent phosphorylation of angulin‐1/LSR is required for the exclusive localization of angulin‐1/LSR and tricellulin at tricellular contacts in EpH4 epithelial sheet

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