mDia2 regulates actin and focal adhesion dynamics and organization in the lamella for efficient epithelial cell migration

Abstract

Cell migration requires spatial and temporal regulation of filamentous actin (F-actin) dynamics. This regulation is achieved by distinct actin-associated proteins, which mediate polymerization, depolymerization, severing, contraction, bundling or engagement to the membrane. Mammalian Diaphanous-related (mDia) formins, which nucleate, processively elongate, and in some cases bundle actin filaments, have been extensively studied in vitro, but their function in the cell has been less well characterized. Here we study the role of mDia2 activity in the dynamic organization of F-actin in migrating epithelial cells. We find that mDia2 localizes in the lamella of migrating epithelial cells, where it is involved in the formation of a stable pool of cortical actin and in maintenance of polymerization-competent free filament barbed ends at focal adhesions. Specific inhibition of mDia2 alters focal adhesion turnover and reduces migration velocity. We suggest that the regulation of filament assembly dynamics at focal adhesions may be necessary for the formation of a stable pool of cortical lamella actin and the proper assembly and disassembly dynamics of focal adhesions, making mDia2 an important factor in epithelial cell migration.

N-cadherin expression level modulates integrin-mediated polarity and strongly impacts on the speed and directionality of glial cell migration

“…These effects might involve the regulation of Src phosphorylation on Y529, which has been shown to influence the dynamics of focal adhesions (Pera et al, 2005;Vielreicher et al, 2007). Increased turnover of focal adhesions might thus be responsible for the effect of N-cadherin on cell migration (Gupton et al, 2007), promoting a faster mesenchymallike migration in a wound-healing assay. In addition, the constitutive engagement of integrins at the cell periphery does not allow further stimulation upon wounding and therefore prevents the generation of wound-induced integrin-mediated signals.…”

Actin nucleators in the nucleus: an emerging theme

“…It is an effector of Rho GTPases and is involved in actin nucleation and elongation and has wide-ranging roles, including contractile ring formation, endocytosis and the formation of lamellipodia and filopodia (Gasman et al, 2003;Pellegrin and Mellor, 2005;Hotulainen and Lappalainen, 2006;Carramusa et al, 2007;Yang et al, 2007;Sarmiento et al, 2008;Watanabe et al, 2008;Ryu et al, 2009). mDia proteins influence cell division and migration and have been implicated in metastasis (Gupton et al, 2007;Yang et al, 2007;Watanabe et al, 2008;Narumiya et al, 2009). Studies also hint at a potential nuclear role for mDia.…”

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

“…mDia formins participate in changes in cell morphology previously thought to depend largely on activated Arp2/3. These processes include the dynamic actin remodeling underlying filopodia/microspike (Tominaga et al, 2002;Peng et al, 2003) and neurite formation (Dent et al, 2007), phagocytosis (ColucciGuyon et al, 2005), vesicle trafficking (Fernandez-Borja et al, 2005;Wallar et al, 2007) and lamella/lamellipodial dynamics Gupton et al, 2007;Yang et al, 2007).…”