Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1964-1977 |
| Number of pages | 14 |
| Journal | Molecular Biology of the Cell |
| Volume | 14 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 1 2003 |
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ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cell Biology
Cite this
P120 catenin is required for growth factor-dependent cell motility and scattering in epithelial cells. / Cozzolino, Mauro; Stagni, Venturina; Spinardi, Laura; Campioni, Nadia; Fiorentini, Carla; Salvati, Erica; Alemà, Stefano; Salvatore, Anna Maria.
In: Molecular Biology of the Cell, Vol. 14, No. 5, 01.05.2003, p. 1964-1977.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - P120 catenin is required for growth factor-dependent cell motility and scattering in epithelial cells
AU - Cozzolino, Mauro
AU - Stagni, Venturina
AU - Spinardi, Laura
AU - Campioni, Nadia
AU - Fiorentini, Carla
AU - Salvati, Erica
AU - Alemà, Stefano
AU - Salvatore, Anna Maria
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0038586464&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0038586464&partnerID=8YFLogxK
U2 - 10.1091/mbc.E02-08-0469
DO - 10.1091/mbc.E02-08-0469
M3 - Article
C2 - 12802068
AN - SCOPUS:0038586464
VL - 14
SP - 1964
EP - 1977
JO - Molecular Biology of the Cell
JF - Molecular Biology of the Cell
SN - 1059-1524
IS - 5
ER -