Steed, E; Elbediwy, A; Vacca, B; Dupasquier, S; Hemkemeyer, SA; Suddason, T; Costa, AC; ... Matter, K; + view all Steed, E; Elbediwy, A; Vacca, B; Dupasquier, S; Hemkemeyer, SA; Suddason, T; Costa, AC; Beaudry, JB; Zihni, C; Gallagher, E; Pierreux, CE; Balda, MS; Matter, K; - view fewer (2014) MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival. Journal of Cell Biology , 204 (5) 821 -838. 10.1083/jcb.201304115.

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Abstract

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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