期刊
JOURNAL OF CELL BIOLOGY
卷 204, 期 5, 页码 821-838出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201304115
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资金
- Biotechnology and Biological Sciences Research Council [BB/J015032/1]
- Wellcome Trust [084678/Z/08/Z, 099173/Z/12/Z, VVT090939MA]
- Cancer Research UK [C26616/A12679]
- Universite Catholique de Louvain (Actions de Recherche Concertees)
- Fonds de la Recherche Scientifique (Belgium)
- Wellcome Trust [084678/Z/08/Z] Funding Source: Wellcome Trust
- BBSRC [BB/J015032/1] Funding Source: UKRI
- MRC [G0400678] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J015032/1] Funding Source: researchfish
- Medical Research Council [G0400678] Funding Source: researchfish
MarvelD3 is a transmembrane component of tight junctions, but there is little evidence for a direct involvement in the junctional permeability barrier. Tight junctions also regulate signaling mechanisms that guide cell proliferation; however, the transmembrane components that link the junction to such signaling pathways are not well understood. In this paper, we show that MarvelD3 is a dynamic junctional regulator of the MEKK1 c-Jun NH2-terminal kinase (JNK) pathway. Loss of MarvelD3 expression in differentiating Caco-2 cells resulted in increased cell migration and proliferation, whereas reexpression in a metastatic tumor cell line inhibited migration, proliferation, and in vivo tumor formation. Expression levels of MarvelD3 inversely correlated with JNK activity, as MarvelD3 recruited MEKK1 to junctions, leading to down-regulation of JNK phosphorylation and inhibition of JNK-regulated transcriptional mechanisms. Interplay between MarvelD3 internalization and JNK activation tuned activation of MEKK1 during osmotic stress, leading to junction dissociation and cell death in MarvelD3-depleted cells. MarvelD3 thus couples tight junctions to the MEKK1 JNK pathway to regulate cell behavior and survival.
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