Rho at the Brake

Abstract

Signaling through the extracellular signal-regulated kinase (ERK) pathway can lead to either cell proliferation or differentiation, and the difference in the outcome appears related to the duration of the ERK signal. Prolonged ERK activity leads to proliferation, whereas transient ERK signaling can lead to differentiation (see Coleman and Marshall). The sustained ERK activity appears to require input both from the cell adhesion pathways, as well as from mitogenic growth factors, and appears to be dependent on the cytoskeleton. Welsh et al . show that inhibition of the Rho family of guanosine triphosphatases (GTPases) (Rho, Rac, and Cdc42) inhibits sustained ERK activity and induction of the expression of the cyclin D1 protein and leads to cell cycle arrest in G 1 . Inhibition of Rho (but not of Rac or Cdc42) blocks sustained ERK activation, but did not inhibit cyclin D1 expression; instead, the rate of cyclin D1 production was enhanced, suggesting that the different members of the Rho family of GTPases have different effects on cyclin D1 production. Indeed transfection of activated forms of Rac or Cdc42 led to the production of cyclin D1 in G 0 and early G 1 , whereas activated Rho did not. The ability of activated Rac or Cdc42 to accelerate cyclin D1 synthesis was independent of ERK signaling, occurring in cells in which the ERK pathway was pharmacologically inhibited, and was independent of signals generated from cell adhesion, occurring in suspended cells. In unattached cells, or cells with a disrupted cytoskeleton, that were stimulated with basic fibroblast growth factor, cyclin D1 expression was not elevated. However, when Rho was inhibited, then cyclin D1 was expressed, suggesting that Rho couples the mitogenic signal to cell adhesion and the cytoskeleton. Rho appears to act as a switch limiting the production of cyclin D1 to the late G 1 phase, possibly by inhibiting pathways downstream of Rac and Cdc42, which would promote premature cyclin D1 expression. M. L. Coleman, C. J. Marshall, A family outing: small GTPases cyclin' through G1. Nature Cell Biol. 3 , E250-E251 (2001). [Online Journal] C. F. Welsh, K. Roovers, J. Villanueva, Y. Liu, M. A. Schwartz, R. K. Assoian, Timing of cyclin D1 expression within G1 phase controlled by Rho. Nature Cell Biol. 3 , 950-957 (2001). [Online Journal]