title: MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival.
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.
authors.affiliation: Department of Cell Biology, Institute of Ophthalmology, University College London, London EC1V 9EL, England, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Steed
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elbediwy
authors.forename: Barbara
authors.initials: B
authors.lastname: Vacca
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dupasquier
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Hemkemeyer
authors.forename: Tesha
authors.initials: T
authors.lastname: Suddason
authors.forename: Ana C
authors.initials: AC
authors.lastname: Costa
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Beaudry
authors.forename: Ceniz
authors.initials: C
authors.lastname: Zihni
authors.forename: Ewen
authors.initials: E
authors.lastname: Gallagher
authors.forename: Christophe E
authors.initials: CE
authors.lastname: Pierreux
authors.forename: Maria S
authors.initials: MS
authors.lastname: Balda
authors.forename: Karl
authors.initials: K
authors.lastname: Matter
mesh_terms: D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D009997:Osmotic Pressure; D019108:Tight Junctions / Q000378:metabolism*
chemical_list: C548163:MARVELD3 protein, human; D008565:Membrane Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human