Rac1 Activation Drives a Nuclear ARM Race

Abstract

Lanning et al. investigated the involvement of RhoA and Rac1 in nuclear transport of the armadillo (ARM) protein SmgGDS and discovered a new role for these two small guanosine triphosphatases (GTPases), as well as a novel mechanism for nuclear transport of ARM proteins. Many ARM family proteins shuttle between the nucleus and cytoplasm, regulating events in both of these compartments. Some ARM proteins contain nuclear localization signal (NLS) sequences or associate with proteins containing NLS sequences; others enter the nucleus through mechanisms that are unclear. SmgGDS is an ARM protein that promotes guanine nucleotide exchange in GTPases with a C-terminal polybasic region (PBR). These include RhoA and Rac1, which are involved in regulating the actin cytoskeleton. Noting the resemblance of the PBR to an NLS, Lanning et al. demonstrated that both fluorescently labeled Rac1 PBR and fluorescently labeled Rac1 accumulated in the nucleus when expressed in CHO-m3 cells. Mutational analysis indicated that Rac1 activation, as well as an intact PBR, promoted nuclear accumulation of Rac1 and of hemagglutinin (HA)-tagged SmgGDS. Rac1 with a mutated PBR promoted nuclear accumulation of SmgGDS less efficiently than did wild-type Rac1 and a dominant negative (DN) Rac1 mutant was ineffective. DN Rac1 containing a mutated PBR diminished accumulation of SmgGDS in the nucleus. Fluorescently labeled RhoA PBR or RhoA showed little nuclear accumulation and inhibited nuclear accumulation of SmgGDS. The authors developed a model whereby SmgGDS associates with and activates Rac1; Rac1 activation and the PBR then promote movement of the complex into the nucleus. RhoA competitively inhibits the association with Rac1, thereby diminishing nuclear accumulation. C. C. Lanning, R. Ruiz-Velasco, C. L. Williams, Novel mechanism of the co-regulation of nuclear transport of SmgGDS and Rac1. J. Biol. Chem . 278 , 12495-12506 (2003). [Abstract] [Full Text]