Tetraspanins Function as Regulators of Cellular Signaling

Abstract

Tetraspanins are molecular scaffolds that distribute proteins into highly organized microdomains consisting of adhesion, signaling, and adaptor proteins. Many reports have identified interactions between tetraspanins and signaling molecules, finding unique downstream cellular consequences. In this review, we will explore these interactions as well as the specific cellular responses to signal activation, focusing on tetraspanin regulation of adhesion-mediated (integrins/FAK), receptor-mediated (EGFR, TNF-α, c-Met, c-Kit), and intracellular signaling (PKC, PI4K, β-catenin). Additionally, we will summarize our current understanding for how tetraspanin post-translational modifications (palmitoylation, N-linked glycosylation, and ubiquitination) can regulate signal propagation. Many of the studies outlined in this review suggest that tetraspanins offer a potential therapeutic target to modulate aberrant signal transduction pathways that directly impact a host of cellular behaviors and disease states.

Keywords: adhesion-mediated signaling; receptor-mediated signal transduction; signal transduction; tetraspanin-enriched microdomains; tetraspanins.

Figure 1

Schematic of tetraspanin molecular structure (Based on Zimmerman et al., 2016). Cartoon depicting the structural characteristics of tetraspanins. Tetraspanins have four transmembrane domains (TM1-TM4), which create one small (EC1) and one large (EC2) extracellular loop as well as a short inner loop. The N- and C-termini of tetraspanins are localized to the intracellular side of the membrane. The Cys-Cys-Gly amino acid motif is depicted in addition to the two characteristic disulfide bonds that are formed in EC2.

Figure 2

CD82 structure and motifs. Cartoon depicting CD82 topology within the plasma membrane and important motifs. CD82 contains five membrane proximal cysteine residues (shown in green) at residues 5, 74, 83, 251, and 253, which can be palmitoylated. There are three asparagine residues in EC2 (shown in orange) that are predicted to be N-linked glycosylated at residues 129, 157, 198. There are four cytoplasmic lysine residues 7, 10, 263, and 266 (shown in gray), which are predicted to be ubiquitinated. The C-terminal tyrosine based sort motif (YXXø) is depicted in blue at amino acids 261–264; for CD82 this motif is Tyr-Ser-Lys-Val.

Figure 3

Tetraspanin enriched microdomains with signaling molecules. Illustration of the plasma membrane depicting tetraspanin interactions with membrane and cytosolic signaling molecules. The downstream signaling consequences attributed to tetraspanin regulation are indicated beneath. Key signaling molecules modulated by tetraspanins include: (A) Adhesion-Mediated Signaling (Integrins/FAK), (B) Receptor-Mediated Signaling (GPCRs, EGFR, c-kit, c-Met, ADAMs, TGF), and (C) Intracellular signaling (PKC, PI4K, Rho-GTPases, and β-catenin).