Activation of the Small GTPase Rac Is Sufficient to Disrupt Cadherin-dependent Cell-Cell Adhesion in Normal Human Keratinocytes

AUTOR(ES)

Braga, Vania M.M.

FONTE

The American Society for Cell Biology

RESUMO

To achieve strong adhesion to their neighbors and sustain stress and tension, epithelial cells develop many different specialized adhesive structures. Breakdown of these structures occurs during tumor progression, with the development of a fibroblastic morphology characteristic of metastatic cells. During Ras transformation, Rac-signaling pathways participate in the disruption of cadherin-dependent adhesion. We show that sustained Rac activation per se is sufficient to disassemble cadherin-mediated contacts in keratinocytes, in a concentration- and time-dependent manner. Cadherin receptors are removed from junctions before integrin receptors, suggesting that pathways activated by Rac can specifically interfere with cadherin function. We mapped an important region for disruption of junctions to the putative second effector domain of the Rac protein. Interestingly, although this region overlaps the domain necessary to induce lamellipodia, we demonstrate that the disassembly of cadherin complexes is a new Rac activity, distinct from Rac-dependent lamellipodia formation. Because Rac activity is also necessary for migration, Rac is a good candidate to coordinately regulate cell-cell and cell-substratum adhesion during tumorigenesis.

Documentos Relacionados

• The Catalytic Activity of the Src Family Kinases Is Required to Disrupt Cadherin-dependent Cell–Cell Contacts
• Small GTPases and regulation of cadherin dependent cell-cell adhesion.
• Microtubule Disruption in Keratinocytes Induces Cell-Cell Adhesion through Activation of Endogenous E-Cadherin
• Loss of E-cadherin-dependent cell-cell adhesion due to mutation of the beta-catenin gene in a human cancer cell line, HSC-39.
• A Novel Role of Nectins in Inhibition of the E-Cadherin–induced Activation of Rac and Formation of Cell-Cell Adherens JunctionsV⃞