IRS-58 Helps Cdc42Hs Reorganize the Cytoskeleton

Abstract

Cdc42Hs, a member of the Rho family of small guanosine triphosphatases (GTPases) is essential for the reorganization of the actin cytoskeleton. Govind et al. used yeast two-hybrid assays to identify a 58-kD insulin receptor substrate adaptor protein (IRS-58) as a new Cdc42Hs-associating protein involved in cytoskeletal reorganization. Overexpression of IRS-58 led to cytoskeletal reorganization, as demonstrated by changes in filamentous (F)-actin structures, focal complexes, and filopodia (in Swiss 3T3 cells), and led to the development of highly branched neurites [in N1E-115 cells (a neuroblastoma cell line)]. Endogenous IRS-58 also localized with F-actin. Cells expressing an IRS-58 mutant that could not bind Cdc42Hs did not form filopodia, indicating that cytoskeletal reorganization depended on the recruitment of Cdc42Hs by IRS-58 to F-actin. Transfection of dominant negative Rac1 mutants in IRS-58-expressing N1E-115 cells did not greatly alter the formation of neurites, suggesting that IRS-58 specifically interacts with Cdc42Hs and not other Rho family members. Thus, IRS-58 seems to function as an adaptor protein on the actin cytoskeleton and recruits the proteins necessary to redirect cytoskeletal reorganization.S. Govind, R. Kozma, C. Monfries, L. Lim, S. Ahmed, Cdc42Hs facilitates cytoskeletal reorganization and neurite outgrowth by localizing the 58-kD insulin receptor substrate to filamentous actin. J. Cell Biol. 152, 579-594 (2001). [Abstract] [Full Text]