PhD Defense: Craig Lefort

Interaction of Tensin and Actin with N-Cadherin-Based Adherens Junction Complexes: Regulation by Fibronectin Matrix Assembly

Abstract

Interactions between the cellular systems that mediate cell adhesion to the extracellular matrix and cell-cell adhesion are essential for the organization of cells into functional tissue. Fibronectin is an adhesive glycoprotein that is polymerized into extracellular matrix fibrils by a tightly-regulated, cell-dependent process. Previous studies indicate that the matrix form of fibronectin enhances cell spreading, growth, and migration. Cell adhesion to the extracellular matrix has been shown to influence cell-cell adhesion mediated by cadherin-based adherens junctions. The purpose of these studies was to determine the role of fibronectin in regulating the composition, organization, and function of N-cadherin-based cell-cell adherens junction complexes.

The interaction of adherens junctions with the actin cytoskeleton of the cell is essential for their adhesive function. Cadherins are thought to associate with actin filaments through the adherens junction protein alpha-catenin, either directly or via actin-binding adaptor proteins. Here, I demonstrate that the actin-binding protein, tensin, is a previously undescribed component of a distinct population of N-cadherin-dependent adherens junctions in fibronectin-null myofibroblasts devoid of fibronectin. The novel quaternary complex contains N-cadherin, beta-catenin, tensin, and actin. The association of tensin or alpha-catenin with N-cadherin-based complexes is mutually exclusive. My data indicate that the matrix form of fibronectin induces the dissociation of tensin and actin from N-cadherin. In addition, extracellular matrix fibronectin stimulates the reorganization of N-cadherin-dependent adherens junctions from peripheral cell-cell contacts into long, thin cellular protrusions. Furthermore, matrix fibronectin inhibits the adhesive function of N-cadherin-dependent adherens junctions.

The mechanisms by which extracellular matrix fibronectin regulates N-cadherin-dependent adherens junctions are discussed. I propose a model in which fibronectin matrix assembly regulates N-cadherin-mediated cell-cell adhesion by stimulating the translocation of tensin from N-cadherin-based adherens junctions to fibrillar adhesions. The dissociation of tensin from N-cadherin-containing complexes in response to fibronectin induces a switch from stable adhesion mediated by tensin-containing adherens junctions to a dynamic form of cell-cell adhesion mediated by alpha-catenin-containing adherens junctions.