[F-actin cappers].

Abstract

Members of a large protein family that cap the barbed (fast-growing) end of actin filament (F-actin) are called F-actin "Cappers". The first F-actin capper called Cap 28/31 is a heterodimer of 28 kDa and 31 kDa proteins, and was isolated from a soil amoeba called Acanthamoeba (Isenberg et al., 1980). F-actin cappers are present in any eucaryotes from yeast to human, and block actin polymerization by capping the fast-growing end of F-actin. In non-stimulated cells, most of the fast-growing ends of actin filaments are capped by an 1:1 complex of actin monomer (G-actin) and profilin, a PIP2-binding protein. When cells are stimulated by one of the mitogenic cytokines such as EGF and PDGF, Ras is activated, and consequently Rac is activated. Rac in turn activates PI-4 kinase which produces PIP2. PIP2 then binds profilin, and dissociates the profilin/G-actin complex, leading to uncapping of the fast-growing end of actin filament, and induces a rapid actin polymerization. Eventually, this results in the induction of membrane ruffling. We found that (1) the Ras/Rac-induced uncapping is required for oncogenicity of Ras, and (2) either capping at the fast-growing end by F-actin cappers such as tensin and cytochalasins, or sequestering PIP2 by PIP2-binders such as cofilin mutants (blocking the uncapping) is sufficient to suppress the malignant transformation caused by oncogenic Ras mutants such as v-Ha-Ras.