Epithelial cadherins are shown to have distinct functions. Using a three-dimensional culture system of epithelial kidney cells, it is shown that cadherin-6 acts as an inhibitor of tubulogenesis, whereas E-cadherin controls lumen formation.

It is crucial for organ homeostasis that epithelia have effective mechanisms to restrict motility and cell proliferation in order to maintain tissue architecture. On the other hand, epithelial cells need to rapidly and transiently acquire a more mesenchymal phenotype, with high levels of cell motility and proliferation, in order to repair epithelia upon injury. Cross talk between cell-cell and cell-matrix signaling is crucial for regulating these transitions. The Pak1-␤PIX-GIT complex is an effector complex downstream of the small GTPase Rac1. We previously showed that translocation of this complex from cell-matrix to cell-cell adhesion sites was required for the establishment of contact inhibition of proliferation. In this study, we provide evidence that this translocation depends on cadherin function. Cadherins do not recruit the complex by direct interaction. Rather, we found that inhibition of the normal function of cadherin or Pak1 leads to defects in focal adhesion turnover and to increased signaling by phosphatidylinositol 3-kinase. We propose that cadherins are involved in regulation of contact inhibition by controlling the function of the Pak1-␤PIX-GIT complex at focal contacts.The maintenance of the highly organized architecture of epithelial cells within a tissue is crucial for epithelial function and organ homeostasis. Epithelial organization is controlled by cell-matrix and cell-cell contacts. Cells can restrict cell migration and proliferation in a cell-cell contact-dependent manner by a process called contact inhibition, which is thought to be a critical process for maintaining epithelial organization. On the other hand, epithelial cells need to retain the ability to transiently acquire a more mesenchymal phenotype, with high levels of cell motility and proliferation, to repair epithelial damage. Since epithelial repair generally occurs by epithelial sheet movements in which cell-cell contacts are still present (16), precise control mechanisms are required to regulate the temporal release of contact inhibition in this process. The molecular mechanisms that control contact inhibition, however, are still not completely understood.Calcium-dependent interactions between the extracellular domains of the adhesion molecule E-cadherin and interactions of ␤-, ␣-, and p120-catenins with its cytoplasmic domain mediate adhesion between adjacent epithelial cells (48). E-cadherin has been implicated in contact inhibition (25,30,38) and likely functions as a tumor suppressor. While contact inhibition may ultimately be regulated by cadherin-mediated upregulation of the cyclin-dependent kinase 2 inhibitor p27 kip1 (25, 38), the intermediate steps between cadherin-mediated cell-cell contact and growth arrest are unclear. The elusive nature of E-cadherin in the regulation of contact inhibition is likely due to the fact that E-cadherin can control cell proliferation by different mechanisms. First, E-cadherin can act via ␤-catenin, which not only functions in cell-cell adhesion, as a component of adherens junctions, b...