Abstract
Cell adhesion to the extracellular matrix is a key event in cell migration and invasion and endocytic trafficking of adhesion receptors and signaling proteins plays a major role in regulating these processes. Beta2-adaptin is a subunit of the AP-2 complex and is involved in clathrin-mediated endocytosis. Herein, β2-adaptin is shown to bind to the focal adhesion protein actopaxin and localize to focal adhesions during cells spreading in an actopaxin dependent manner. Furthermore, β2-adaptin is enriched in adhesions at the leading edge of migrating cells and depletion of β2-adaptin by RNAi increases cell spreading and inhibits directional cell migration via a loss of cellular polarity. Knockdown of β2-adaptin in both U2OS osteosarcoma cells and MCF10A normal breast epithelial cells promotes the formation of matrix degrading invadopodia, adhesion structures linked to invasive migration in cancer cells. These data therefore suggest that actopaxin-dependent recruitment of the AP-2 complex, via an interaction with β2-adaptin, to focal adhesions mediates cell polarity and migration and that β2-adaptin may control the balance between the formation of normal cell adhesions and invasive adhesion structures.
Highlights
Directed cell migration is a highly coordinated and dynamic process that involves polarization of the cell in response to an external stimulus, followed by the extension of membrane protrusions in the direction of migration [1]
Using an antibody that recognizes both the b1- and b2-adaptin components of the AP-1 and adaptor protein-2 complex (AP-2) complexes, we found that endogenous b-adaptin, which binds directly to clathrin, localizes to paxillin positive focal adhesion structures during U2OS osteosarcoma cell spreading on a collagen matrix (Figure 1A)
Beta2-adaptin localized to focal adhesions during cell spreading and migration in an actopaxin-dependent fashion
Summary
Directed cell migration is a highly coordinated and dynamic process that involves polarization of the cell in response to an external stimulus, followed by the extension of membrane protrusions in the direction of migration [1]. Integrins cluster and form multiprotein assemblies, consisting of signaling, adaptor and structural proteins that mediate physical links to the actin cytoskeleton, These structures, called focal adhesions provide the traction forces required for efficient cell motility to occur and act as signaling hubs that integrate the multiple regulatory pathways involved in the coordination of the cell migration machinery [2,3]. Proteins associated with the regulation of clathrin-mediated endocytosis may play key roles in the regulation of adhesion turnover and signaling during adhesion-dependent events such as cell migration and invasion. Beta2-adaptin knockdown resulted in the generation of matrixdegrading adhesions termed invadopodia, typically found in cancer cells [20,21] These data suggest a role for b2-adaptin in the regulation of adhesion related signaling required for directed cell migration and matrix degradation
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