8.A.177.  The Tumor Necrosis Factor Ligand Member 6 (TNFL6) Family

The TNFL6/FAS protein (CD95L) activates the NHE1 Na⁺/H⁺ exchanger, NHE1 (TC# 2.A.36, a plasma membrane protein that is ubiquitously present in all human cells) (Monet et al. 2016). It functions to regulate intracellular pH removing an intracellular proton in exchange for one extracellular sodium and is involved in heart disease and in promoting metastasis in cancer (Fliegel 2021). 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 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, and disruption of the Akt and ROCK1 phosphorylation sites on NHE1 decreases cell migration in cells exposed to cl-CD95L. Thus, NHE1 is a molecular actor in the CD95 signaling pathway that drives the cl-CD95L-induced cell migration through both the Akt and RhoA signaling pathways (Monet et al. 2016).