Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
ISSN: 0043-1648

hal-01679411
https://hal.univ-antilles.fr/hal-01679411
DOI : 10.1016/j.wear.2004.11.019

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
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.
ISSN: 2045-2322

hal-01334067
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01334067
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01334067/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01334067/file/Cleaved%20FAS%20ligand%20CC-BY.pdf
DOI : 10.1038/srep28008

Éditeur(s) : HAL CCSD American Association for Cancer Research
Résumé : International audience
Triple-negative breast cancers (TNBC) lacking estrogen and progesterone receptors and HER2 amplification have a relatively high risk of metastatic dissemination, but the mechanistic basis for this risk is not understood. Here we report that serum levels of CD95L are higher in TNBC patients compared to other breast cancer patients. Metalloprotease-mediated cleavage of CD95L expressed by endothelial cells surrounding tumors generates a gradient that promotes cell motility, due to formation of an unconventional CD95-containing receptosome termed the motility-inducing signaling complex. Formation of this complex was instrumental for Nox3-driven ROS generation. Mechanistic investigations revealed a Yes-Orai1-EGFR-PI3K pathway that triggered migration of TNBC cells exposed to CD95L. Our findings establish a pro-metastatic function for metalloprotease-cleaved CD95L in triple-negative breast cancers, revisiting its role in carcinogenesis.
ISSN: 0008-5472

hal-00873634
https://hal.archives-ouvertes.fr/hal-00873634
PUBMED : 24072745
DOI : 10.1158/0008-5472.CAN-13-1794

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
CD95 ligand (CD95L) is expressed by immune cells and triggers apoptotic death. Metalloprotease-cleaved CD95L (cl-CD95L) is released into the bloodstream but does not trigger apoptotic signaling. Hence, the pathophysiological role of cl-CD95L remains unclear. We observed that skin-derived endothelial cells from systemic lupus erythematosus (SLE) patients expressed CD95L and that after cleavage, cl-CD95L promoted T helper 17 (Th17) lymphocyte transmigration across the endothelial barrier at the expense of T regulatory cells. T cell migration relied on a direct interaction between the CD95 domain called calcium-inducing domain (CID) and the Src homology 3 domain of phospholipase C gamma 1. Th17 cells stimulated with cl-CD95L produced sphingosine-1-phosphate (S1P), which promoted endothelial transmigration by activating the S1P receptor 3. We generated a cell-penetrating CID peptide that prevented Th17 cell transmigration and alleviated clinical symptoms in lupus mice. Therefore, neutralizing the CD95 non-apoptotic signaling pathway could be an attractive therapeutic approach for SLE treatment.
ISSN: 1074-7613

hal-01359568
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01359568
DOI : 10.1016/j.immuni.2016.06.028
PUBMED : 27438772

Éditeur(s) : HAL CCSD Taylor & Francis Open
Résumé : International audience
Our recent findings indicate that cells exposed to transmembrane (m-CD95L) or metalloprotease-cleaved CD95L (cl-CD95L) undergo a localized Ca(2+)entry that not only inhibits the initial steps of the CD95-mediated apoptotic signal but also promotes cell motility. Based on recent findings published on the non-apoptotic signals induced by CD95, we discuss how m-CD95L and cl-CD95L diverging by their stoichiometry could both contribute to the immune response by first recruiting activated T lymphocytes in the inflamed area and later by eliminating infected and transformed cells.
ISSN: 1942-0889

hal-00873761
https://hal.archives-ouvertes.fr/hal-00873761
https://hal.archives-ouvertes.fr/hal-00873761/document
https://hal.archives-ouvertes.fr/hal-00873761/file/The_CD95_signaling_pathway-accepted.pdf
DOI : 10.4161/cib.18888