Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K.
Transformation of mammary epithelial cells into invasive carcinoma results in alterations in their integrin-mediated responses to the extracellular matrix, including a loss of normal epithelial polarization and differentiation, and a switch to a more motile, invasive phenotype. Changes in the actin cytoskeleton associated with this switch suggest that the small GTPases Cdc42 and Rac, which regulate actin organization, might modulate motility and invasion. However, the role of Cdc42 and Rac1 in epithelial cells, especially with respect to integrin-mediated events, has not been well characterized. Here we show that activation of Cdc42 and Rac1 disrupts the normal polarization of mammary epithelial cells in a collagenous matrix, and promotes motility and invasion. This motility does not require the activation of PAK, JNK, p70 S6 kinase, or Rho, but instead requires phosphatidylinositol-3-OH kinase (PI(3)K). Further, direct PI(3)K activation is sufficient to disrupt epithelial polarization and induce cell motility and invasion. PI(3)K inhibition also disrupts actin structures, suggesting that activation of PI(3)K by Cdc42 and Rac1 alters actin organization, leading to increased motility and invasiveness.
Keely
P J
PJ
Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599-7365, USA. pkeely@med.unc.edu
Westwick
J K
JK
Whitehead
I P
IP
Der
C J
CJ
Parise
L V
LV
D000199:Actins / Q000378:metabolism; D001940:Breast / Q000166:cytology; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic; D004848:Epithelium; D020558:GTP Phosphohydrolases / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D020846:cdc42 GTP-Binding Protein, Saccharomyces cerevisiae; D020744:rac GTP-Binding Proteins
D000199:Actins; D018797:Cell Cycle Proteins; D019869:Phosphatidylinositol 3-Kinases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020846:cdc42 GTP-Binding Protein, Saccharomyces cerevisiae; D020744:rac GTP-Binding Proteins