ERRα coordinates actin and focal adhesion dynamics

Abstract

Cell migration depends on the dynamic organization of the actin cytoskeleton and assembly and disassembly of focal adhesions (FA). However the precise mechanisms coordinating these processes remain poorly understood. We previously identified the estrogen-related receptor (ERR) as a major regulator of cell migration. Here, we show that loss of ERR leads to abnormal accumulation of actin filaments that is associated with an increase in the level of inactive form of the actin-depolymerizing factor cofilin. We further show that ERR depletion decreases cell adhesion and promotes defective FA formation and turnover. Interestingly, specific inhibition of the RhoA-ROCK-LIMK-cofilin pathway rescues the actin polymerization defects resulting from ERR silencing, but not cell adhesion. Instead we found that MAP4K4 is a direct target of ERR and down-regulation of its activity rescues cell adhesion and FA formation in the ERR-depleted cells. Altogether, our results highlight a crucial role of ERR in coordinating the dynamic of actin network and focal adhesion through the independent regulation of the RhoA and MAP4K4 pathways.