Catenins Steer Cell Migration via Stabilization of Front-Rear Polarity

Abstract

Cell migration plays a pivotal role in morphogenetic and pathogenetic processes. To achieve directional migration, cells must establish a front-to-rear axis of polarity. Here we show that components of the cadherin-catenin complex function to stabilize this front-rear polarity. Neural crest and glioblastoma cells undergo directional migration in vivo or in vitro. During this process, αE-catenin accumulated at lamellipodial membranes and then moved toward the rear with the support of a tyrosine-phosphorylated β-catenin. This relocating αE-catenin bound to p115RhoGEF, leading to gathering of active RhoA in front of the nucleus where myosin-IIB arcs assemble. When catenins or p115RhoGEF were removed, cells lost the polarized myosin-IIB assembly, as well as the capability for directional movement. These results suggest that, apart from its well-known function in cell adhesion, the β-catenin/αE-catenin complex regulates directional cell migration by restricting active RhoA to perinuclear regions and controlling myosin-IIB dynamics at these sites.

Myosin II isoforms play distinct roles in adherens junction biogenesis

“…Interestingly, in the absence of α-catenin KD, the localization of NMIIB was not restricted any more to junctional membranes in early epithelial junctions. Instead, NMIIB co-assembled with NMIIA on the same actin fibres, likely in heretotypic minifilaments, as observed in previous studies 36,61 , indicating that α-catenin is responsible for the junctional recruitment of NMIIB, as reinforced by a recent publication reporting NMIIB and α-catenin interaction in glioblastoma cells 73 .…”

“…These differential distributions at the early stages of AJ formation were not specific to MDCK cells, and were observed as well in small clusters of Caco2 cells (Supplementary Fig.3e). Considering recent findings showing a possible interaction between NMIIB and α-catenin 73 , we hypothesized that NMIIB could be recruited to the junction through α-catenin/E-cadherin complexes. Accordingly, in α-catenin KD MDCK cells 74 , NMIIB was relocalized to NMIIA-enriched stress fibres and circumnuclear actin cables (Fig.…”

“…On the other hand, junctional tension has been shown to associate with the presence of α-catenin molecules under open conformations 78,79 . Moreover, a direct link between α-catenin and NMIIB has been reported 73 , suggesting that NMIIB recruitment, α-catenin molecular unfolding and regulation of Arp2/3-dependent branched actin polymerization could be tightly linked. Thus, we performed immunostainings with the α18 monoclonal antibody recognizing the open conformation of the protein 79 .…”

“…Given that E-cadherin complexes have been shown to biochemically interact with both Arp2/3 16,77 and NMIIB 73 , one hypothesis could be that NMIIB and Arp2/3 are both recruited to E-cadherin/catenin complexes upon cell-cell contact initiation. NMIIB could thus serve as a cross-linker of the junctional actin network.…”

Endosomal spatio-temporal modulation of the cortical RhoA zone conditions epithelial cell organization

“…mCherry-tagged AHPH partially overlaps with total Rho-GFP (Supplementary Figure 8a) and significantly co-distributes with location biosensors of the RhoA effectors ROCK1 and mDia (ROCK1-GBD-GFP, based on the GTP-RhoA binding domain of ROCK1, and mDia-GBD-GFP, based on the GTP-RhoA binding domain of mDia) (Supplementary Figure 8b-c) (Budnar et al, 2019). Moreover, the expression of an AHPH mutated form in the RBD domain, unable to bind GTP-RhoA (AHPH A740D -GFP), generates a different intracellular pattern than the wt AHPH form (Supplementary Figure 8d) (Priya et al, 2015; Vassilev et al, 2017). These data testify of the specificity of AHPH-tagged for RhoA-GTP signal and confirm that it can be faithfully used to probe RhoA-GTP dynamics.…”