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 sphingolipid 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. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.

Keywords: Ceramide; Ezrin; Moesin; Radixin; Sphingolipids; Sphingosine-1-phosphate.

Figure 1. Sphingolipid metabolic pathway

This figure illustrates the sphingolipid metabolic pathway described in the text along with the structure of each product. It emphasizes the opposing roles played by two major bioactive products of sphingolipid metabolism, ceramide and sphingosine-1-phosphate. While ceramide is known to play a role in cell cycle arrest and apoptosis, S1P is known to be involved in promoting cell proliferation, inflammation, migration, and invasion. Glu (Glucose), Gal (Galactose), GCS (Glucosylceramide Synthase), GBA (Glucocerebrosidase), CK (ceramide kinase), SMS (sphingomyelin synthase), SMase (sphingomyelinase), CDase (Ceramidase), CerS (Ceramide Synthase), SK (sphingosine kinase), S1PPase (S1P Phosphatase).

Figure 2. Sphingolipid regulation of ERM activation

This figure illustrates the mechanism of ERM regulation by sphingolipids on the tip of a cellular extension. Cisplatin causes activation of the acid sphingomyelinase (aSMase), which causes ceramide production. Ceramide activates protein phosphatase 2A (PP2A) to cause ezrin dephosphorylation and detachment from the cell membrane. Alternatively, the use of bacterial sphingomyelinase causes activation of protein phosphatase 1 alpha (PP1a) to cause ezrin dephosphorylation. In contrast, S1P, generated after bacterial ceramidase use (bCDase) or after EGF treatment translocates to the extracellular space using one of the described transporters such as the ABC transporter to activate sphingosine-1-phosphate receptor 2 (S1P2). S1P2 signaling activates a yet unknown kinase to cause ezrin phosphorylation and binding to the plasma membrane using phosphatidylinositol biphosphate (PIP2).