p120 catenin regulates the actin cytoskeleton via Rho family GTPases.
Cadherins are calcium-dependent adhesion molecules responsible for the establishment of tight cell-cell contacts. p120 catenin (p120ctn) binds to the cytoplasmic domain of cadherins in the juxtamembrane region, which has been implicated in regulating cell motility. It has previously been shown that overexpression of p120ctn induces a dendritic morphology in fibroblasts (Reynolds, A.B. , J. Daniel, Y. Mo, J. Wu, and Z. Zhang. 1996. Exp. Cell Res. 225:328-337.). We show here that this phenotype is suppressed by coexpression of cadherin constructs that contain the juxtamembrane region, but not by constructs lacking this domain. Overexpression of p120ctn disrupts stress fibers and focal adhesions and results in a decrease in RhoA activity. The p120ctn-induced phenotype is blocked by dominant negative Cdc42 and Rac1 and by constitutively active Rho-kinase, but is enhanced by dominant negative RhoA. p120ctn overexpression increased the activity of endogenous Cdc42 and Rac1. Exploring how p120ctn may regulate Rho family GTPases, we find that p120ctn binds the Rho family exchange factor Vav2. The behavior of p120ctn suggests that it is a vehicle for cross-talk between cell-cell junctions and the motile machinery of cells. We propose a model in which p120ctn can shuttle between a cadherin-bound state and a cytoplasmic pool in which it can interact with regulators of Rho family GTPases. Factors that perturb cell-cell junctions, such that the cytoplasmic pool of p120ctn is increased, are predicted to decrease RhoA activity but to elevate active Rac1 and Cdc42, thereby promoting cell migration.
Department of Cell Biology and Anatomy and the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
N K
NK
Noren
B P
BP
Liu
K
K
Burridge
B
B
Kreft
D000199:Actins / Q000378:metabolism* / Q000648:ultrastructure; D015820:Cadherins / Q000096:biosynthesis / Q000235:genetics; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002465:Cell Movement; D048429:Cell Size; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D004789:Enzyme Activation; D007365:Intercellular Junctions; D008954:Models, Biological; D015513:Oncogene Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics; D051567:Proto-Oncogene Proteins c-vav; D011994:Recombinant Proteins / Q000096:biosynthesis; D013489:Suppression, Genetic; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000095002:Delta Catenin
D000199:Actins; D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; D015513:Oncogene Proteins; D010750:Phosphoproteins; D051567:Proto-Oncogene Proteins c-vav; D011994:Recombinant Proteins; C093651:VAV2 protein, human; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000095002:Delta Catenin