Regulation of Cell-Cell Adhesion by Abi/Diaphanous Complexes

Abstract

Actin polymerization provides the driving force for the formation of cell-cell junctions and is mediated by two types of actin nucleators, Arp2/3 and formins. Proteins required for coordinately linking cadherin-mediated adhesion to Arp2/3-dependent versus formin-dependent nucleation have yet to be defined. Here we show a role for Abi, the Abi-binding partner Nap1, and the Nap1-binding protein Sra1 in the regulation of cadherindependent adhesion. We found that Abi, which is known to interact with Wave, leading to activation of the Arp2/3 complex, is also capable of interacting with the Diaphanous (Dia)-related formins in the absence of Wave. Knockdown of Abi, Nap1, Sra1, or Dia markedly inhibited cell-cell junctions, whereas knockdown of Wave or Arp2/3 produced mild and transient phenotypes. Dia and Abi colocalized with ␤-catenin at cell-cell junctions. Further, Dia and Wave bound to overlapping sites on Abi1, and Wave competed with Dia for Abi1 binding. Notably, an active Dia1 C-terminal fragment that localizes to cell-cell junctions rescued the abnormal junctions induced by depletion of Abi or Nap1 in epithelial cells. These findings uncover a novel link between cadherin-mediated adhesion and the regulation of actin dynamics through the requirement for an Abi/Dia complex for the formation and stability of cell-cell junctions.

Changes in E-cadherin rigidity sensing regulate cell adhesion

“…In particular, formin activity, which polymerizes long, parallel actin bundles found in filopodia (46, 47), appeared to be essential for cell adhesion and dynamic filopodialike protrusions on a 30-kPa Ecad-Fc PA gel, but not on a 60-kPa Ecad-Fc PA gel. These results are consistent with previous studies that demonstrated a role for the diaphanous formin mDia1 (11,65,66) and formin-like proteins FMNL2 and FMNL3 (12,13) in the recruitment of actin and E-cadherin and the formation of filopodia at initial cell-cell contacts. At present, we do not know which formin(s) is (are) regulated by the stiffness of E-cadherin interactions.…”

Spatial integration of E-cadherin adhesion, signalling and the epithelial cytoskeleton

“…Formins promote F-actin elongation as linear filaments [4]. The family members mDia1 [22,23] and FMNL2 [24] are necessary for Ecadherin stabilization at junctions. Constitutive activation of FMNL2 or mDia1 increases F-actin levels at cell-cell contacts [22,24]; yet they are regulated by different GTPases.…”

Essential role for Abi1 in embryonic survival and WAVE2 complex integrity

“…Dictyostelium has only one Abi gene; thus it offers no specific conclusion for roles of mammalian Abi1 or Abi2. Moreover, numerous studies have concluded that Abi proteins have overlapping functions in actin cytoskeleton regulation (29,30). Studies using conventional Abi1 (31) and WAVE2 (16) mutant alleles suggested a critical role of Abi1 in embryonic development, thus suggesting that a conditional allele would provide more definitive information about Abi1, including its function in adult organs.…”