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.

Adhesion molecules in gamete transport, fertilization, early embryonic development, and implantation—role in establishing a pregnancy in cattle: A review

“…This creates molecular links whereby the intracellular region of cadherins can influence the activity of the extracellular region (Nagafuchi & Takeichi, 1988; Kintner, 1992). Intracellular α‐catenin is essential for cadherin function as cells that express cadherin but lack α‐catenin do not show cell–cell adhesion and cell signaling properties (Termini & Gillette, 2017). Similar to other families of adhesion molecules (ADAMs, integrins), altered function of cadherins can be associated with tumor growth and metastasis (Sousa et al, 2019).…”

“…The action of integrins includes interaction with the integrin‐associated cell‐surface protein tetraspanin CD9 (Reyes et al, 2018; Termini & Gillette, 2017; Zhu & Evans, 2002; Ziyyat et al, 2006; Figure 2). A role for CD9 in the attachment of sperm ADAM2 to oocyte α 6 β 1 was demonstrated in mice using CD9 knockout models (Kaji et al, 2000; Miyado et al, 2000; Le Naour, Rubinstein, Jasmin, Prenant, & Boucheix, 2000) and with the use of monoclonal antibodies to CD9 (M. S. Chen et al, 1999; Stein, Primakoff, & Myles, 2004).…”

Non‐IgE mediated mast cell activation

“…Tetraspanins consist of 4 transmembrane domains with an evolutionary conserved structure, connected both intracellularly and extracellularly by loops . They function as molecular scaffold by bringing together different molecules of signaling cascades thereby amplifying their activity .…”

“…Tetraspanins consist of 4 transmembrane domains with an evolutionary conserved structure, connected both intracellularly and extracellularly by loops . They function as molecular scaffold by bringing together different molecules of signaling cascades thereby amplifying their activity . Tetraspanins and associated proteins exhibit several cellular functions, for example, modulation of intercellular immune interactions including adhesion, migration, organizing membrane signaling complexes, facilitate intracellular protein transport, and function as chaperons .…”

Tspan15 Is a New Stemness‐Related Marker in Hepatocellular Carcinoma

“…Tetraspanins may regulate the expression, trafficking, activity, and function of their molecular partners. Furthermore, tetraspanins exhibit the property to associate with each other and play a role as organizers of the plasma membrane by the compartmentalization of numerous membrane proteins including adhesion molecules, signaling proteins, trafficking molecules, membrane proteases, and growth factor receptors into microdomains so called tetraspanin‐enriched microdomains …”