Function and regulation of RhoE.

The three Rnd proteins, Rnd1, Rnd2 and RhoE/Rnd3, are a subset of Rho family proteins that are unusual in that they bind but do not hydrolyse GTP, and are therefore not regulated by the classical GTP/GDP conformational switch of small GTPases. Increased expression of each Rnd protein induces loss of stress fibres in cultured fibroblasts and epithelial cells, acting antagonistically to RhoA, which stimulates stress fibre formation. RhoE is farnesylated and localizes partly on membranes, including the Golgi and plasma membrane, and in the cytosol. RhoE inhibits RhoA signalling in part by binding to the RhoA-activated serine/threonine kinase ROCK I (Rho-associated kinase I), thereby preventing it from phosphorylating its targets. RhoE activity is itself regulated by phosphorylation by ROCK I on multiple sites. RhoE phosphorylation enhances its stability, leading to an increase in RhoE levels. In addition, phosphorylation reduces its association with membranes and correlates with its ability to induce loss of stress fibres. RhoE also acts independently of ROCK to inhibit cell cycle progression, in part by preventing translation of cyclin D1, and to inhibit transformation of fibroblasts by oncogenic H-Ras. RhoE is therefore a multifunctional protein whose localization and actions are regulated by phosphorylation.

[1]  P. Scambler,et al.  RhoE Regulates Actin Cytoskeleton Organization and Cell Migration , 1998, Molecular and Cellular Biology.

[2]  A. Ridley,et al.  RhoE Binds to ROCK I and Inhibits Downstream Signaling , 2003, Molecular and Cellular Biology.

[3]  R. Stancou,et al.  Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes. , 1996, The EMBO journal.

[4]  C. Pineau,et al.  Rho family GTPase Rnd2 interacts and co-localizes with MgcRacGAP in male germ cells. , 2003, The Biochemical journal.

[5]  J. Settleman,et al.  Rnd Proteins Function as RhoA Antagonists by Activating p190 RhoGAP , 2003, Current Biology.

[6]  K. Mori,et al.  Socius Is a Novel Rnd GTPase-Interacting Protein Involved in Disassembly of Actin Stress Fibers , 2002, Molecular and Cellular Biology.

[7]  J. Settleman,et al.  Identification of a novel human Rho protein with unusual properties: GTPase deficiency and in vivo farnesylation , 1996, Molecular and cellular biology.

[8]  H. Ozaki,et al.  Up-regulation of Rnd1 during pregnancy serves as a negative-feedback control for Ca2+ sensitization of contractile elements in rat myometrium. , 2003, Biochemical and biophysical research communications.

[9]  W. Pledger,et al.  Paradigms of Growth Control: Relation to Cdk Activation , 2002, Science's STKE.

[10]  C J Marshall,et al.  Post-translational modifications of p21rho proteins. , 1992, The Journal of biological chemistry.

[11]  K. Aktories,et al.  Rho-modifying C3-like ADP-ribosyltransferases. , 2004, Reviews of physiology, biochemistry and pharmacology.

[12]  P. Adamson,et al.  Intracellular localization of the P21rho proteins , 1992, The Journal of cell biology.

[13]  H. Katoh,et al.  A Role of Rnd1 GTPase in Dendritic Spine Formation in Hippocampal Neurons , 2003, The Journal of Neuroscience.

[14]  W. Gold,et al.  A novel gene family induced by acute inflammation in endothelial cells. , 2004, Gene.

[15]  I. Vetter,et al.  Crystal structure of Rnd3/RhoE: functional implications 1 , 2002, FEBS letters.

[16]  M. Mattei,et al.  A New Member of the Rho Family, Rnd1, Promotes Disassembly of Actin Filament Structures and Loss of Cell Adhesion , 1998, The Journal of cell biology.

[17]  A. Ridley,et al.  RhoE function is regulated by ROCK I‐mediated phosphorylation , 2005, The EMBO journal.

[18]  M. Riese,et al.  Bacterial toxins that modify the actin cytoskeleton. , 2002, Annual review of cell and developmental biology.

[19]  Anne J. Ridley,et al.  ROCKs: multifunctional kinases in cell behaviour , 2003, Nature Reviews Molecular Cell Biology.

[20]  A. Ridley,et al.  Crystal structure of the core domain of RhoE/Rnd3: a constitutively activated small G protein. , 2002, Biochemistry.

[21]  K. Mori,et al.  Vps4-A (vacuolar protein sorting 4-A) is a binding partner for a novel Rho family GTPase, Rnd2. , 2002, The Biochemical journal.

[22]  A. Ridley,et al.  RhoE Inhibits Cell Cycle Progression and Ras-Induced Transformation , 2004, Molecular and Cellular Biology.

[23]  P. Pacaud,et al.  Modulation of RhoA—Rho kinase‐mediated Ca2+ sensitization of rabbit myometrium during pregnancy — role of Rnd3 , 2003, The Journal of physiology.