Evidence for Dsg3 in regulating Src signaling by competing with it for binding to caveolin-1

Abstract

This data article contains extended, complementary analysis related to the research articles entitled “Desmoglein 3, via an interaction with E-cadherin, is associated with activation of Src” (Tsang et al., 2010) [1] and figures related to the review article entitled “Desmoglein 3: a help or a hindrance in cancer progression?” (Brown et al., 2014) [2]. We show here that both Src and caveolin-1 (Cav-1) associate with Dsg3 in a non-ionic detergent soluble pool and that modulation of Dsg3 levels inversely alters the expression of Src in the Cav-1 complex. Furthermore, immunofluorescence analysis revealed a reduced colocalization of Cav-1/total Src in cells with overexpression of Dsg3 compared to control cells. In support, the sequence analysis has identified a region within the carboxyl-terminus of human Dsg3 for a likelihood of binding to the scaffolding domain of Cav-1, the known Src binding site in Cav-1, and this region is highly conserved across most of 18 species as well as within desmoglein family members. Based on these findings, we propose a working model that Dsg3 activates Src through competing with its inactive form for binding to Cav-1, thus leading to release of Src followed by its auto-activation.

Altered Cell-Cycle Control, Inflammation, and Adhesion in High-Risk Persistent Bronchial Dysplasia

“…The structural roles of these factors suggest that increased expression could contribute to squamous metaplastic change that may be more prominent in persistent disease and thus represent potential markers of high risk BD. DSG3 is a key component of desmosomes which sequesters pro-oncogenic desmosomal components associated with epithelial to mesenchymal transition, but has recently also been associated with non-desmosomal cytoplasmic activation of pro-tumorigenic SRC signaling (42). Indeed, overexpression of DSG3 has been described in lung cancer and has been associated with poor prognosis in esophageal SCC and pancreatic adenocarcinoma (43–45).…”

Dbf4

“…The cytoplasmic tail consists of several domains, such as the intracellular anchoring domain (IA), intracellular cadherin-specific domain (ICS), proline-rich linker domain (IPL), repeating unit domain (RUD), and lastly the desmoglein-specific terminal domain (DTD). The proteins that have been identified to directly bind to the cytoplasmic domain of Dsg3 includes p120 that binds to IA, plakoglobin (Pg) and caveolin-1 (Cav-1) that bind to ICS, and actin with the specific domain not yet defined (Andl and Stanley 2001;Brown et al 2014;Wan et al 2016;Kanno et al 2008). The evidence for the interaction with actin proteins came from the mass spectrometry analysis of the Halo immunoprecipitates from A431 cells transfected with plasmid containing the entire Dsg3 cytoplasmic tail tagged with Halo at the N-terminus (Brown et al 2014).…”

“…Caveolae is thought to modulate signal transduction through the compartmentalization of specific signaling molecules and regulation of their activity (Lisanti et al 1994). Emerging evidence suggests that both Src and Cav-1 associate with Dsg3 and a modulation of Dsg3 levels (overexpression or knockdown) causes an inverse effect on the amount of Src molecules bound to Cav-1 (Wan et al 2016). In support, a potential binding site for the scaffolding domain of Cav-1 is identified within the C-terminus of human Dsg3 at amino acids 788-798 that contain four aromatic amino acid residues (Wan et al 2016), and this region shares some common feature with the characterized amino acid sequence that binds to the scaffolding domain of Cav-1 (Couet et al 1997).…”

“…Emerging evidence suggests that both Src and Cav-1 associate with Dsg3 and a modulation of Dsg3 levels (overexpression or knockdown) causes an inverse effect on the amount of Src molecules bound to Cav-1 (Wan et al 2016). In support, a potential binding site for the scaffolding domain of Cav-1 is identified within the C-terminus of human Dsg3 at amino acids 788-798 that contain four aromatic amino acid residues (Wan et al 2016), and this region shares some common feature with the characterized amino acid sequence that binds to the scaffolding domain of Cav-1 (Couet et al 1997). It is worth noting that this region is highly conserved within the desmoglein subfamily members (Dsg1-4) as well as across most of 18 species (Wan et al 2016).…”

DOCK2; Dedicator of Cytokinesis 2

“…Furthermore, it has been proposed that the Dsg3mediated Src activation likely involves Cav-1, a scaffolding protein in a special type of lipid raft known as caveolae (Fig. 4), and the D overexpression of Dsg3 leads to its competition with the inactive form of Src for binding to Cav-1, thus causing the release of Src followed by its autoactivation (Wan et al 2016). Cav-1 is known to negatively regulate the Src activity through an inhibitory interaction which prevents its autophosphorylation (Li et al 1996;Okamoto et al 1998).…”