Sphingolipid regulation of ezrin, radixin, and moesin proteins family: Implications for cell dynamics

Abstract

A key but poorly studied domain of sphingolipid functions encompasses endocytosis, exocytosis, cellular trafficking, and cell movement. Recently, the ezrin, radixin and moesin (ERM) family of proteins emerged as novel potent targets regulated by sphingolipids. ERMs are structural proteins linking the actin cytoskeleton to the plasma membrane, also forming a scaffold for signaling pathways that are used for cell proliferation, migration, and invasion, and cell division. Opposing functions of the bioactive sphingolipids ceramide and sphingosine-1-phosphate (S1P), contribute to ERM regulation. S1P robustly activates whereas ceramide potently deactivates ERM via phosphorylation/dephosphorylation, respectively. This recent dimension of cytoskeletal regulation by sphingolipids opens up new avenues to target cell dynamics, and provides further understanding of some of the unexplained biological effects mediated by sphingolipids. In addition, these studies are providing novel inroads into defining basic mechanisms of regulation and action of bioactive sphingolipids. This review describes the current understanding of sphingolipid regulation of the cytoskeleton, it also describes the biologies in which ERM proteins have been involved, and finally how these two large fields have started to converge.

Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

“…The first study that promoted this conceptual shift appeared in the mid-eighties, when sphingosine had been shown to inhibit PKC activity (Hannun et al, 1986). Since then several downstream protein effectors have been described or suggested mainly for sphingosine, ceramide, ceramide-1-phosphate, glycosphingolipids, and sphingosine-1-phosphate (Adada et al, 2014;Arana et al, 2013;Pontier and Schweisguth, 2012).…”

Upregulation of NHE1 protein expression enables glioblastoma cells to escape TMZ-mediated toxicity via increased H+extrusion, cell migration and survival

“…ERM proteins play an important role in cancer migration and invasion and interact with NHE1 protein in migration (27). We speculate that increased NHE1 protein expression may alter its interaction with the ERM complex and promote glioma migration.…”

Slp2-a inactivates ezrin by recruiting protein phosphatase 1 to the plasma membrane

“…In the present study, we discovered a novel function of the Slp2-a linker domain in the control of ezrin activity. Slp2-a was found to interact via its previously uncharacterized linker domain with PP1b, which is known to inactivate ezrin through dephosphorylation at Thr-567 [21] (Fig. 4), and to recruit PP1b to the plasma membrane of MDCK II cells (Fig.…”

“…Reports of two recent studies, one demonstrating that both PP1 and PP2 have the ability to dephosphorylate ezrin at threonine 567 [21], and the other showing that PP1 interacts with Slp2-a in vitro [22], prompted us to further investigate the possible involvement of PPs in Slp2-a-mediated ezrin inactivation. Consistent with the results of these previous studies, the results of our coimmunoprecipitation assays in COS-7 cells indicated that all three isoforms of the catalytic subunits of PP1, but neither of the catalytic subunits of PP2s, interacted with Slp2-a (Fig.…”