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First published online March 12, 2004
doi: 10.1242/10.1242/jcs.01118

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Rho-family GTPases: it's not only Rac and Rho (and I like it)

Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA

View larger version (20K): [in a new window]   Fig. 1. Post-translational modification and expression patterns of Rho proteins. (A) Representation of the different C-termini, the post-translational lipid modifications that occur at these sites in Rho proteins, and the additional membrane targeting signals. The first four represent variations seen in CAAX motif-terminating Rho GTPases. The CAAX sequence signals for either farnesyl (F) or geranylgeranyl (GG) isoprenoid modification of the cysteine residue, followed by proteolytic removal of the AAX residues, and carboxylmethylation (OMe) of the now-terminal cysteine residue. Rac1 (also Rac2, Rac3, RhoA, RhoC and Cdc42) has a polybasic [K/R] sequence followed by a GG-modified cysteine. Rnd proteins contain a polybasic sequence followed by an F modification of the cysteine. TC10 (and probably TCL) is modified by both F and a palmitoyl (P) group. RhoB is modified by a P group at one cysteine and either a F or GG group at the other cysteine. RhoD is also F-modified, whereas Rif is expected to be GG-modified. These modifications have been verified by direct or indirect analyses (Adamson et al., 1992b; Ando et al., 1992; Foster et al., 1996; Michaelson et al., 2001; Murphy et al., 1996; Yamane et al., 1991). RhoBTB, which does not undergo any known post-translational modifications, contains two BTB domains C-terminal of the GTPase domain, and does not terminate with a CAAX motif. Miro contains two EF-hand (EFH) motifs and one additional GTPase domain that are C-terminal of the Rho GTPase-like domain, and does not terminate with a CAAX motif. (B) A summary of expression patterns, regulated expression and post-translational modifications of the Rho-family proteins. The post-translational modifications that have not been experimentally verified are marked with a `?'. Abbreviations: Hp, hematopoietic; Br, brain; He, heart; Pl, placenta; Pa, pancreas; Sm, skeletal muscle; Lu, lung; Li, liver; Sp, spleen; Te, testis.

View larger version (26K): [in a new window]   Fig. 2. Phylogenetic tree of the Rho-family GTPases and representatives of other Ras-superfamily GTPases. A phylogenetic analysis of the amino acid sequences of the Rho domains of the 22 Rho-family members made with ClustalW, together with functional data (see text) shows that the family can be roughly divided into six major branches: RhoA-related, Rac-related, Cdc42-related, Rnd proteins, RhoBTB proteins and Miro proteins.

View larger version (120K): [in a new window]   Fig. 3. Sequence alignment of the Rho family. The amino acid sequences of the 22 described Rho-family gene members (main isoforms) were aligned by ClustalW. Highlighted are residues important for GTPase activity (cyan), the core effector domain (pink), the Rho insert domain (red), and prenylation motifs (yellow: geranylgeranyl; blue: farnesyl; green: geranylgeranyl or farnesyl). Note that the amino acid sequences of RhoBTB-1, RhoBTB-2, Miro-1 and Miro-2 have been truncated in the C-termini. The protein sequences used correspond to the following accession numbers (from top to bottom): NP_001655, NP_786886, NP_004031, NP_055393, NP_061907, NP_005431, NP_005159, NP_055285, NP_008839, NP_002863, NP_005043, NP_001656, NP_001782, NP_036381, NP_065714, NP_598378, NP_067028, NP_055651, NP_055993, NP_004301, NP_060777 and NP_620124.

View larger version (20K): [in a new window]   Fig. 4. Examples of Rho regulation by membrane localization. (A) Schematic presentation of elements in Rho that dictate membrane targeting. (B) Membrane delivery of Rho protein by Rho-complexed RhoGDI binding to target molecules at specific membrane sites followed by release of Rho protein to the membrane. (C) The polybasic domain found in some Rho-family proteins provides a second signal that dictates membrane localization. The components in the membranes (here depicted as `X' and `Y') that specifically bind to and localize each Rho protein (here examplified by the names `Rho1' and `Rho2') are unknown. Abbreviations: PM, plasma membrane; EM, endomembrane.