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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).

References associated with 8.A.177 family:

Fliegel, L. (2021). Role of Genetic Mutations of the Na/H Exchanger Isoform 1, in Human Disease and Protein Targeting and Activity. Mol. Cell Biochem 476: 1221-1232. 33201382
Madaio, M.P., I. Czikora, N. Kvirkvelia, M. McMenamin, Q. Yue, T. Liu, H.A. Toque, S. Sridhar, K. Covington, R. Alaisami, P.M. O''Connor, R.W. Caldwell, J.K. Chen, M. Clauss, M.W. Brands, D.C. Eaton, M.J. Romero, and R. Lucas. (2019). The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis. Kidney Int 95: 1359-1372. 30905471
Martin-Malpartida, P., S. Arrastia-Casado, J. Farrera-Sinfreu, R. Lucas, H. Fischer, B. Fischer, D.C. Eaton, S. Tzotzos, and M.J. Macias. (2022). Conformational ensemble of the TNF-derived peptide solnatide in solution. Comput Struct Biotechnol J 20: 2082-2090. 35601958
Monet, M., M. Poët, S. Tauzin, A. Fouqué, A. Cophignon, D. Lagadic-Gossmann, P. Vacher, P. Legembre, and L. Counillon. (2016). The cleaved FAS ligand activates the Na+/H+ exchanger NHE1 through Akt/ROCK1 to stimulate cell motility. Sci Rep 6: 28008. 27302366