p120 Catenin is required for growth factor-dependent cell motility and scattering in epithelial cells.
Cadherin-mediated cell-cell adhesion is dynamically modulated during epithelial-mesenchymal transition triggered by activation of receptor tyrosine kinases (RTK) in epithelial cells. Several cadherin-binding proteins have been identified that control cell-cell adhesion. However, the mechanisms by which intercellular adhesion and cell motility are coregulated are still unknown. Here, we delineate a hitherto uncharted cooperation between RTKs, RhoA GTPase, and p120 catenin in instructing a motile behavior to epithelial cells. We found that expression of an N-terminus-deleted p120 catenin in a variety of epithelial cell types, including primary keratinocytes, effectively competes for endogenous p120 at cadherin binding sites and abrogates EGF-stimulated cell motility as well as HGF-induced cell scattering. The deleted mutant also inhibits the PI3K-dependent RhoA activation ensuing receptor activation. Conversely, we also show that the ectopic expression of full-length p120 in epithelial cells promotes cytoskeletal changes, stimulates cell motility, and activates RhoA. Both motogenic response to p120 and RhoA activation require coactivation of signaling downstream of RTKs as they are suppressed by ablation of the Ras/PI3K pathway. These studies demonstrate that p120 catenin is a necessary target of RTKs in regulating cell motility and help define a novel pathway leading to RhoA activation, which may contribute to the early steps of metastatic invasion.
Cozzolino
Mauro
M
Istituto di Neurobiologia e Medicina Molecolare, CNR, 00137 Rome, Italy.
Stagni
Venturina
V
Spinardi
Laura
L
Campioni
Nadia
N
Fiorentini
Carla
C
Salvati
Erica
E
Alemà
Stefano
S
Salvatore
Anna Maria
AM
D000818:Animals; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000095002:Delta Catenin
D051177:Catenins; D015815:Cell Adhesion Molecules; D010750:Phosphoproteins; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D020744:rac GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000095002:Delta Catenin; C000722349:Ctnnd1 protein, mouse