Atypical Rho Family Members
Of the 20 Rho GTP-binding proteins in humans, 8 have atypical properties, which are also unusual within the Ras superfamily. These atypical proteins fall into four subfamilies: RhoU/RhoV, Rnd1/Rnd2/Rnd3, RhoH and RhoBTB1/RhoBTB2. These proteins are known
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Atypical Rho Family Members Barbara Borda-d’Agua, Elvira Infante, Philippe Riou, Virginia Tajadura, and Anne J. Ridley
Abstract Of the 20 Rho GTP-binding proteins in humans, 8 have atypical properties, which are also unusual within the Ras superfamily. These atypical proteins fall into four subfamilies: RhoU/RhoV, Rnd1/Rnd2/Rnd3, RhoH and RhoBTB1/ RhoBTB2. These proteins are known or predicted to be predominantly GTP-bound in cells, because of changes in their ability to exchange GDP for GTP or to hydrolyse GTP. Apart from RhoH, they also have N-terminal and C-terminal extensions that give them unique interacting partners and functions. For example, RhoU can bind SH3 domain-containing proteins, Rnd proteins can bind to 14-3-3 proteins, and RhoBTB proteins can interact via their BTB domains with cullin-3, which is involved in proteasomal degradation. The proteins have been implicated in diverse functions, including cell adhesion and migration, vesicle trafficking and cell proliferation. Keywords RhoU/RhoV • RhoH • Rnd proteins • RhoBTB proteins • Cytoskeleton • Cell cycle
B. Borda-d’Agua • A.J. Ridley (*) Randall Division of Cell and Molecular Biophysics, King’s College London, New Hunt’s House, Guy’s Campus, London SE1 1UL, UK e-mail: [email protected] E. Infante Institut Curie - Membrane and Cytoskeleton Dynamics, CNRS UMR 144, 75005, Paris, France P. Riou Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK V. Tajadura Division of Cancer Studies, King’s College London, Thomas Guy House, Guy’s Campus, London SE1 9RT, UK A. Wittinghofer (ed.), Ras Superfamily Small G Proteins: Biology and Mechanisms 1, DOI 10.1007/978-3-7091-1806-1_15, © Springer-Verlag Wien 2014
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Introduction
Twelve of the 20 Rho family GTP-binding proteins in humans cycle between a GTP-bound active form and a GDP-bound inactive form and are regulated by GEFs, GAPs and in some cases RhoGDIs. The other 8 family members are considered non-classical because they do not appear to be regulated in the same way, and also have unique N-terminal and C-terminal extensions to the standard G-domain. These atypical Rho members fall into two categories. First, RhoU and RhoV have a high intrinsic nucleotide exchange rate in vitro, which means they are mostly GTP-bound in cells and unlikely to be regulated by GEFs. Second, the Rnd (Rnd1, Rnd2 and Rnd3/RhoE), RhoH and RhoBTB proteins (RhoBTB1 and RhoBTB2) have amino acid substitutions that prevent them from hydrolysing GTP. These amino acid substitutions are at the equivalent amino acids that are mutated in Ras oncogenes, and known to prevent/reduce GTP hydrolysis, so that the proteins are constitutively GTP-bound. This means that they are regulated in different ways to the GTP/GDP switch. Of the non-classical Rho proteins, Rnd3 was the first to be discovered, when it was cloned as a p190RhoGAP-interacting protein in 1996 (Foster et al. 1996). Here we describe the structure and function of the eight non-classical Rho proteins.
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