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.
Highlights
Tetraspanins are membrane-spanning proteins with a conserved structure that function primarily as membrane protein organizers
This study provides substantial evidence that the roles of tetraspanins CD9, CD81, and CD151 are unique in their regulation of PKCα-integrin interactions
Using quantitative FRET imaging and KG1a acute myeloid leukemia (AML) cell lines that overexpress wild type CD82 or a palmitoylation deficient form of CD82 (Delandre et al, 2009), we found that upon phorbol 12-myristate 13-acetate (PMA) stimulation, PKCα was recruited to the plasma membrane where it associates with CD82
Summary
Tetraspanins are membrane-spanning proteins with a conserved structure that function primarily as membrane protein organizers. CD82 knockdown altered the EGFR diffusion patterns on the plasma membrane and reduced ERK phosphorylation upon EGF stimulation, providing evidence that tetraspanins can regulate the spatial dynamics of proteins for controlling downstream signaling. The regulatory mechanism remains unknown, this study provides a clear indication that tetraspanins can modulate c-Met mediated signaling downstream of integrin engagement It was shown through immunoprecipitation studies that CD82 and c-Met interact (Takahashi et al, 2007). As tetraspanins can regulate PKC and MAPK signaling (Zhang et al, 2001; Termini et al, 2016), a closer examination into the interplay between these molecules in mediating TGFα signaling may provide a more comprehensive view of the complex regulatory networks at play within TEMs. A follow up study demonstrated that CD9 expression enhances TGF-α expression at the cell surface using MDCK cells (Imhof et al, 2008). Future studies may focus on determining how CD151 modulates the molecular organization of the TGF receptor, as this may provide a mechanism to regulate downstream signaling
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