Overlapping functions of Ras and Rac GTPases in regulating cancer cell proliferation and invasion.

The mechanism by which the Ras and Rac GTPases and the mitogen activated protein kinase cascade regulate cancer cell proliferation and invasion has been an intense area of investigation. A great diversity of membrane receptors and upstream regulators activate the Ras and Rac GTPases. It has been recognized that Ras and Rac GTPases regulate a set of cellular responses including gene expression, cellular proliferation and motility. In human cancer, constitutively active Ras mutations may contribute to deregulated cell proliferation and invasion. Rac has been shown to be an essential partner in Ras-mediated transformation. While these studies have been very important in increasing our understanding of the roles of Ras and Rac, many human cancer cells do not contain Ras and Rac mutations yet show increased activation of the downstream target ERK1, proliferate rapidly in vitro and in vivo and readily penetrate semipermeable membranes. We characterized human squamous cell carcinoma lines that do not contain H-Ras or Rac1 mutations but express high levels of activated ERK1. To delineate the functions of Ras and Rac in these cells, we were able to stably express dominant negative Ras and Rac1 constructs in one of these lines. Both dominant negative Ras and Rac1 constructs inhibited proliferation of these clones by regulating a similar set of cell cycle proteins. Both dominant negative constructs inhibited basal and growth factor-induced levels of cellular migration. We concluded that Ras and Rac1 have overlapping functions in cancer cell proliferation and migration.