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Anoikis Mediated by Stress-Activated MAPK Signaling Pathways

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Anoikis

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Abstract

The JUN NH2-terminal kinases (JNKs) and p38 mitogen-activated protein kinases (MAPKs) represent a group of signaling enzymes that are collectively named stress-activated MAPKs. Recent studies of epithelial cells have demonstrated that both of these signaling pathways promote detachment-induced cell death (anoikis) in vitro and in vivo. The p38 MAPK pathway phosphorylates activating transcription factor 2 (ATF2) and increases expression of the JUN transcription factor that promotes expression of the pro-apoptotic BCL2 family member BIM. The JNK signaling pathway causes phosphorylation of the transcription factor JUN and similarly causes increased BIM expression. JNK also causes pro-apoptotic phosphorylation of the BIM-related protein BMF and inhibitory phosphorylation of the anti-apoptotic protein MCL1. The JNK and p38 MAPK signaling pathways therefore function co-operatively and non-redundantly to increase BIM and BMF apoptotic activity. The mechanism of cell death is mediated by the BAX/BAK-dependent intrinsic cell death pathway. Blocking either the JNK or the p38 MAPK pathway suppresses epithelial cell anoikis in vitro and prevents luminal clearance of mammary epithelial ducts in vivo.

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Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, Boston, MA, 02115, USA

    Nomeda Girnius

  2. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA

    Roger J. Davis

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  1. WVU Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, WV, USA

    Steven M. Frisch

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Girnius, N., Davis, R.J. (2021). Anoikis Mediated by Stress-Activated MAPK Signaling Pathways. In: Frisch, S.M. (eds) Anoikis. Springer, Cham. https://doi.org/10.1007/978-3-030-73856-3_8

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