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

TLDR

Members of the Rho family of small GTPases—Rho, Rac, and Cdc42—regulate actin cytoskeleton organization, with Rho forming stress fibers and focal adhesions, Rac promoting lamellipodia and membrane ruffles, and Cdc42 inducing filopodia. Microinjection of Rho, Rac, or Cdc42 into quiescent fibroblasts drives G1 progression and DNA synthesis, whereas dominant‑negative Rac/Cdc42 or the Rho inhibitor C3 block serum‑induced DNA synthesis; these GTPases do not activate the canonical MAPK cascade but Rac and Cdc42 stimulate JNK/SAPK, underscoring their essential role in cell‑growth signaling.

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 NH 2 -terminal kinase or stress-activated protein kinase). Rho, Rac, and Cdc42 control signal transduction pathways that are essential for cell growth.