α-Catenin Controls the Anisotropy of Force Distribution at Cell-Cell Junctions during Collective Cell Migration

Abstract

Adherens junctions (AJs) control epithelial cell behavior, such as collective movement and morphological changes, during development and in disease. However, the molecular mechanism of AJ remodeling remains incompletely understood. Here, we report that the conformational activation of α-catenin is the key event in the dynamic regulation of AJ remodeling. α-catenin activates RhoA to increase actomyosin contractility at cell-cell junctions. This leads to the stabilization of activated α-catenin, in part through the recruitment of the actin-binding proteins, vinculin and afadin. In this way, α-catenin regulates force sensing, as well as force transmission, through a Rho-mediated feedback mechanism. We further show that this is important for stable directional alignment of multiple cells during collective cell movement by both experimental observation and mathematical modeling. Taken together, our findings demonstrate that α-catenin controls the establishment of anisotropic force distribution at cell junctions to enable cooperative movement of the epithelial cell sheet.

Afadin regulates actomyosin organization through αE-catenin at adherens junctions

“…The β-catenin–fused αE-catenin (β/α-cat) lacks the N domain–mediated dimerization activity and shows only a weak FAB activity, as well as that of the β-catenin–αE-catenin complex ( Bianchini et al, 2015 ; Yamada et al, 2005 ). αE-catenin exists as a conformationally closed form, in which the MI subdomain is stabilized and thereby masked by the subdomains containing the MII and MIII subdomains and the binding of vinculin to the MI subdomain of the closed form is inhibited, unless force is exerted ( Hirano et al, 2018 ; Maki et al, 2016 ; Matsuzawa et al, 2018 ; Yonemura et al, 2010 ). Point mutations in the MI subdomain (M319G/R326E) destabilize the MI subdomain to make αE-catenin conformationally open, enhancing its binding of vinculin ( Maki et al, 2016 ; Matsuzawa et al, 2018 ).…”

Cell–cell adhesion: linking Wnt/β-catenin signaling with partial EMT and stemness traits in tumorigenesis

“…In inflammatory breast cancer (IBC), CTC clusters that enhance metastasis are organized as intra-lymphatic tumor cell emboli that retain membrane-bound E-cadherin, maintain cell–cell adhesion, and invade as clusters that display a partial EMT (characterized by vimentin expression) 34 . Invasion via CTC clusters can also involve the activation of α-catenin, another adherens junction plaque protein that promotes the contractility of the actomyosin system in cell–cell junctions 35 . Cancer cells expressing E-cadherin were recently shown to form heterotypic adhesion complexes with cancer-associated fibroblasts that express N-cadherin, thereby assisting in cancer cell migration 36 .…”

Vinculin anchors contractile actin to the cardiomyocyte adherens junction

“…AJ binding capabilities are modified by the forces of actomyosin contraction, largely through changes in -catenin conformation (Hoffman and Yap, 2015;Charras and Yap, 2018). Force induces a conformational change in the central M-domain of E-catenin to reveal binding sites for ligands, many of which bind F-actin (le Duc et al, 2010;Yonemura et al, 2010;Choi et al, 2012;Yao et al, 2014;Kim et al, 2015;Matsuzawa et al, 2018). The force required to unfurl E-catenin (5pN) is well within the range of a myosin motor, demonstrating the physiological relevance for this model of regulation (Finer et al, 1994;Charras and Yap, 2018).…”

“…Vinculin and afadin are recruited to epithelial AJs in a force-dependent manner (le Duc et al, 2010;Yonemura et al, 2010;Kale et al, 2018;Matsuzawa et al, 2018). Vinculin and afadin localize to the ICD in adult heart and proximity proteomics revealed that both are enriched at the AJ in cultured neonatal cardiomyocytes (Li et al, 2019).…”

“…In epithelia, vinculin is recruited to E-catenin in a forcedependent manner and this interaction is thought to be important for reinforcing the E-catenin:actin interaction (le Duc et al, 2010;Yonemura et al, 2010;Kale et al, 2018). Likewise, epithelial afadin can also bind E-catenin in a force-dependent manner (Matsuzawa et al, 2018), where it functions to strengthen the AJ under tension (Choi et al, 2016). Both vinculin and afadin localize to the ICD (Geiger et al, 1985;Borrmann et al, 2006) and are recruited to cardiomyocyte AJs (Li et al, 2019).…”