An Essential Role for Rho, Rac, and Cdc42 GTPases in Cell Cycle Progression Through G ₁

Abstract

Members of the Rho family of small guanosine triphosphatases (GTPases) regulate the organization of the actin cytoskeleton; Rho controls the assembly of actin stress fibers and focal adhesion complexes, Rac regulates actin filament accumulation at the plasma membrane to produce lamellipodia and membrane ruffles, and Cdc42 stimulates the formation of filopodia. When microinjected into quiescent fibroblasts, Rho, Rac, and Cdc42 stimulated cell cycle progression through G1 and subsequent DNA synthesis. Furthermore, microinjection of dominant negative forms of Rac and Cdc42 or of the Rho inhibitor C3 transferase blocked serum-induced DNA synthesis. Unlike Ras, none of the Rho GTPases activated the mitogen-activated protein kinase (MAPK) cascade that contains the protein kinases c-Raf1, MEK (MAPK or ERK kinase), and ERK (extracellular signal-regulated kinase). Instead, Rac and Cdc42, but not Rho, stimulated a distinct MAP kinase, the c-Jun kinase JNK/SAPK (Jun NH2-terminal kinase or stress-activated protein kinase). Rho, Rac, and Cdc42 control signal transduction pathways that are essential for cell growth.

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action

“…Activation of ER by Brx was not a ected by dominant negative mutants of Rac-1, RhoA, or by C3 transferase expression; in agreement with studies documenting distinct signal transduction pathways for these Rho family members (Coso et al, 1995;Minden et al, 1995;Olson et al, 1995). Rac and Cdc42Hs, originally reported to regulate actin cytoskeletal organization, were more recently shown to interact with proteins involved in mitogenesis and to a ect nuclear signaling through activation of transcription by serum response factor (SRF) (Hill et al, 1995), JNK (Coso et al, 1995;Minden et al, 1995;Olson et al, 1995), and pp70 S6K (Chou and Blenis, 1996). The data presented here expand the set of proteins in¯uenced by Cdc42 to include a liganddependent transcription factor, the estrogen receptor.…”

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

“…The myc-tagged dominantnegative Rac1 (N17) was a gift from Dr A Hall (SloanKettering Institute, New York, NY, USA) (Olson et al, 1995), and dominant-negative Cdc42 (N17) and RhoA (N19) (Olson et al, 1995) were obtained from UMR cDNA Resource Center (Rolla, MO, USA). The IL2R/E-cadherin membrane proximal chimera construct was provided by Dr C Gottardi (Northwestern University, Chicago, IL, USA) (Miranda et al, 2001).…”

Regulation of cell proliferation by G proteins

“…It appears that the signals from Ga 12/13 are translated into growth-promoting signals by the small GTPases Ras, Rac, and Rho. It has been reported that Ras, Rho, Rac, and CDC42 play an essential role in cell cycle progression from G1 to S phase (Aktas et al, 1997;Takuwa and Takuwa, 1997;Olson et al, 1995;Hirai et al, 1997). An additional role for Rac in progression from G2 to M phase has been also identi®ed (Moore et al, 1997).…”