Anoikis Mediated by Stress-Activated MAPK Signaling Pathways

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.