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MarvelD3 couples tight junctions to the MEKK1–JNK pathway to regulate cell behavior and survival

2014; Rockefeller University Press; Volume: 204; Issue: 5 Linguagem: Inglês

10.1083/jcb.201304115

1540-8140

Emily Steed, Ahmed Elbediwy, Barbara Vacca, Sébastien Dupasquier, Sandra A. Hemkemeyer, Tesha Suddason, Ana Catarina Costa, Jean–Bernard Beaudry, Ceniz Zihni, Ewen Gallagher, Christophe E. Pierreux, María S. Balda, Karl Matter,

S100 Proteins and Annexins

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.