SGEF forms a complex with Scribble and Dlg1 and regulates epithelial junctions and contractility

Abstract

The canonical Scribble polarity complex is implicated in regulation of epithelial junctions and apical polarity. Here, we show that SGEF, a RhoG-specific GEF, forms a ternary complex with Scribble and Dlg1, two members of the Scribble complex. SGEF targets to apical junctions in a Scribble-dependent fashion and functions in the regulation of actomyosin-based contractility and barrier function at tight junctions as well as E-cadherin–mediated formation of adherens junctions. Surprisingly, SGEF does not control the establishment of polarity. However, in 3D cysts, SGEF regulates the formation of a single open lumen. Interestingly, SGEF’s nucleotide exchange activity regulates the formation and maintenance of adherens junctions, and in cysts the number of lumens formed, whereas SGEF’s scaffolding activity is critical for regulation of actomyosin contractility and lumen opening. We propose that SGEF plays a key role in coordinating junctional assembly and actomyosin contractility by bringing together Scribble and Dlg1 and targeting RhoG activation to cell–cell junctions.

The Scribble family in cancer: twentieth anniversary

“…Crystal structure and quantitative binding data revealed that Scribble PDZ1 and PDZ3 domains display the highest affinity for the β-PIX PDZBM, whereas PDZ2 displays a 20-fold weaker affinity, and PDZ4 none [29]. Scribble also forms a ternary complex with Dlg1 and SGEF, a RhoG-specific GEF, at cell-cell junctions through the PDZ1 of Scribble and an atypical internal PDZBM in SGEF [45].…”

Scribble and discs-large direct initial assembly and positioning of adherens junctions during establishment of apical-basal polarity

“…Métais et al, 2005;Navarro et al, 2005). In MDCK cells, Scrib knockdown reduces Ecad-based adhesion and Ecad retention at AJs, and delays polarization, potentially via effects on p120-Ecad interactions and the Rho-GEF SGEF (Awadia et al, 2019;Lohia et al, 2012;Qin et al, 2005). Scrib also regulates polarization of MCF7 cells in 3D cysts (Hendrick et al, 2016).…”

ARHGEF26 enhancesSalmonellainvasion and inflammation in cells and mice

“…Our third hypothesis is that ARHGEF26 may have impacts on Salmonella invasion independent of its GEF activity. This is based on work from one of our labs that demonstrated that some of ARHGEF26's cellular roles involve forming a tertiary complex with DLG1 and SCRIB independent of nucleotide exchange (48). (49), as well as in regulating epithelial junctions formation, contractability, and 352 lumen formation in 3D cysts (48).…”

“…This is based on work from one of our labs that demonstrated that some of ARHGEF26's cellular roles involve forming a tertiary complex with DLG1 and SCRIB independent of nucleotide exchange (48). (49), as well as in regulating epithelial junctions formation, contractability, and 352 lumen formation in 3D cysts (48). With this in mind, we investigated whether DLG1 and/or 353 SCRIB has a role in Salmonella invasion.…”

“…Involvement of DLG1 and SCRIB in ARHGEF26-mediated Salmonella invasion 402 could be facilitated by one of two mechanisms. First, DLG1 and SCRIB could help 403 ARHGEF26 localize to the site of invasion in order to serve as a GEF, similar to how they 404 function to drive adherens junction formation (48). Alternatively, formation of the 405 ARHGEF26, DLG1, SCRIB tertiary complex could drive Salmonella invasion through 406 unknown and GEF-independent mechanisms, as one of our labs described for 407 actomyosin contractility (48).…”