The cleaved FAS ligand activates the Na(+)/H(+) exchanger NHE1 through Akt/ROCK1 to stimulate cell motility.
Transmembrane CD95L (Fas ligand) can be cleaved to release a promigratory soluble ligand, cl-CD95L, which can contribute to chronic inflammation and cancer cell dissemination. The motility signaling pathway elicited by cl-CD95L remains poorly defined. Here, we show that in the presence of cl-CD95L, CD95 activates the Akt and RhoA signaling pathways, which together orchestrate an allosteric activation of the Na(+)/H(+) exchanger NHE1. Pharmacologic inhibition of Akt or ROCK1 independently blocks the cl-CD95L-induced migration. Confirming these pharmacologic data, disruption of the Akt and ROCK1 phosphorylation sites on NHE1 decreases cell migration in cells exposed to cl-CD95L. Together, these findings demonstrate that NHE1 is a novel molecular actor in the CD95 signaling pathway that drives the cl-CD95L-induced cell migration through both the Akt and RhoA signaling pathways.
Université Nice-Sophia Antipolis, CNRS UMR7370 LP2M, Faculté de Médecine, 28 Avenue de Valombrose 06107 Nice cedex. France and Laboratories of Excellence Ion Channel Science and Therapeutics, France.
Michael
M
Monet
Université Nice-Sophia Antipolis, CNRS UMR7370 LP2M, Faculté de Médecine, 28 Avenue de Valombrose 06107 Nice cedex. France and Laboratories of Excellence Ion Channel Science and Therapeutics, France.
Mallorie
M
Poët
Université Rennes-1, Inserm U1085, 2 Av du Prof. Léon Bernard, 35043, Rennes, France.
Sébastien
S
Tauzin
Centre Eugène Marquis, Inserm ER440, Oncogenesis Stress and Signaling, Equipe Labellisée Ligue Contre Le Cancer "Death Receptors and Tumor Escape", rue bataille Flandres-Dunkerque, 35042 Rennes, France.
Amélie
A
Fouqué
Université Nice-Sophia Antipolis, CNRS UMR7370 LP2M, Faculté de Médecine, 28 Avenue de Valombrose 06107 Nice cedex. France and Laboratories of Excellence Ion Channel Science and Therapeutics, France.
Auréa
A
Cophignon
Université Rennes-1, Inserm U1085, 2 Av du Prof. Léon Bernard, 35043, Rennes, France.
Dominique
D
Lagadic-Gossmann
Université de Bordeaux, Inserm U1045, 146 rue Léo Saignat, 33046 Bordeaux, France.|Bergonié Cancer Institute, 33000 Bordeaux, France.
Pierre
P
Vacher
Centre Eugène Marquis, Inserm ER440, Oncogenesis Stress and Signaling, Equipe Labellisée Ligue Contre Le Cancer "Death Receptors and Tumor Escape", rue bataille Flandres-Dunkerque, 35042 Rennes, France.
Patrick
P
Legembre
Université Nice-Sophia Antipolis, CNRS UMR7370 LP2M, Faculté de Médecine, 28 Avenue de Valombrose 06107 Nice cedex. France and Laboratories of Excellence Ion Channel Science and Therapeutics, France.
Laurent
L
Counillon
D002460:Cell Line; D002465:Cell Movement; D053222:Fas Ligand Protein / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011522:Protons; D015398:Signal Transduction; D000074082:Sodium-Hydrogen Exchanger 1 / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D011522:Protons; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; C066737:RHOA protein, human; D051057:Proto-Oncogene Proteins c-akt; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein