Small GTP-binding proteins. Physiol Rev

Department of Molecular Biology, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita, Japan.
Physiological Reviews (Impact Factor: 27.32). 02/2001; 81(1):153-208.
Source: PubMed


Small GTP-binding proteins (G proteins) exist in eukaryotes from yeast to human and constitute a superfamily consisting of more than 100 members. This superfamily is structurally classified into at least five families: the Ras, Rho, Rab, Sar1/Arf, and Ran families. They regulate a wide variety of cell functions as biological timers (biotimers) that initiate and terminate specific cell functions and determine the periods of time for the continuation of the specific cell functions. They furthermore play key roles in not only temporal but also spatial determination of specific cell functions. The Ras family regulates gene expression, the Rho family regulates cytoskeletal reorganization and gene expression, the Rab and Sar1/Arf families regulate vesicle trafficking, and the Ran family regulates nucleocytoplasmic transport and microtubule organization. Many upstream regulators and downstream effectors of small G proteins have been isolated, and their modes of activation and action have gradually been elucidated. Cascades and cross-talks of small G proteins have also been clarified. In this review, functions of small G proteins and their modes of activation and action are described.

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    • "The reciprocal NMR studies of effector binding to RAS and its oncogenic mutants, where RAS is isotopically enriched, established a hierarchy of effector binding to HRAS in which BRAF RBD displayed the highest-affinity binding, and provide an elegant approach for directly monitoring the complex RAS signaling network (Smith and Ikura, 2014; Smith et al., 2013). The RAS subfamily of guanine nucleotide-binding proteins (G proteins), comprising three major isoforms in humans (HRAS, KRAS, and NRAS), are small monomeric GTPases that play a critical role in numerous signal transduction pathways associated with cell growth and differentiation, and many human cancers (Stephen et al., 2014; Takai et al., 2001). RAS proteins function as molecular switches, oscillating between inactive GDP-bound and active GTP-bound states; the latter can bind and activate a variety of effector proteins and signaling pathways . "
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    ABSTRACT: RAS binding is a critical step in the activation of BRAF protein serine/threonine kinase and stimulation of the mitogen-activated protein kinase signaling pathway. Mutations in both RAS and BRAF are associated with many human cancers. Here, we report the solution nuclear magnetic resonance (NMR) and X-ray crystal structures of the RAS-binding domain (RBD) from human BRAF. We further studied the complex between BRAF RBD and the GppNHp bound form of HRAS in solution. Backbone, side-chain, and (19)F NMR chemical shift perturbations reveal unexpected changes distal to the RAS-binding face that extend through the core of the RBD structure. Moreover, backbone amide hydrogen/deuterium exchange NMR data demonstrate conformational ensemble changes in the RBD core structure upon complex formation. These changes in BRAF RBD reveal a basis for allosteric regulation of BRAF structure and function, and suggest a mechanism by which RAS binding can signal the drastic domain rearrangements required for activation of BRAF kinase. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Structure 07/2015; 23(8). DOI:10.1016/j.str.2015.06.003 · 5.62 Impact Factor
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    • "The target proteins have a consensus CAAX motif (where C represents cysteine, A represents aliphatic amino acid, and X preferentially represents leucine or phenylalanine) at the C-terminus (Lane & Beese 2006). Because our intention of isolating vic mutants is to identify new components that act in the Pmk1 MAPK pathway, we assumed that one of the attractive candidate targets of Cwg2 responsible for the vic phenotype on mutation would be Rho-family members based on the conserved roles of Rho proteins as upstream activators of the MAPK signaling (Takai et al. 2001). In fission yeast, among the six Rho-family proteins, Rho1, Rho4, Rho5 and Cdc42 small GTPases contain CAAL motif modified by GGTase I (Fig. 2A). "
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    ABSTRACT: Pmk1, a fission yeast homologue of mammalian ERK MAPK, regulates cell wall integrity, cytokinesis, RNA granule formation and ion homeostasis. Our screen for vic (viable in the presence of immunosuppressant and chloride ion) mutants identified regulators of the Pmk1 MAPK signaling, including Cpp1 and Rho2, based on the genetic interaction between calcineurin and Pmk1 MAPK. Here, we identified the vic2-1 mutants carrying a mis-sense mutation in the cwg2(+) gene encoding a beta subunit of geranylgeranyltransferase I (GGTase I), which participates in the post-translational C-terminal modification of several small GTPases, allowing their targeting to the membrane. Analysis of the vic2-1/cwg2-v2 mutant strain showed that the localization of Rho1, Rho4, Rho5 and Cdc42, both at the plasma and vacuolar membranes, was impaired in the vic2-1/cwg2-v2 mutant cells. In addition, Rho4 and Rho5 deletion cells exhibited the vic phenotype and cell wall integrity defects, shared phenotypes among the components of the Pmk1 MAPK pathway. Consistently, the phosphorylation of Pmk1 MAPK on heat shock was decreased in the cwg2-v2 mutants, and rho4- and rho5-null cells. Moreover, Rho4 and Rho5 associate with Pck1/Pck2. Possible roles of Cwg2, Rho4 and Rho5 in the Pmk1 signaling will be discussed. © 2015 The Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.
    Genes to Cells 02/2015; 20(4). DOI:10.1111/gtc.12222 · 2.81 Impact Factor
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    • "New options require an improved understanding of smooth muscle contraction and growth in the prostate, and identification of new targets (Hennenberg et al., 2014a). Besides Rac, the superfamily of small monomeric GTPases comprises at least 25 members, including RhoA, amongst others (Takai et al., 2001; Wennerberg and Der, 2004). While the role of RhoA in smooth muscle contraction in different organs, including the prostate, has been intensively studied (Christ and Andersson, 2007; Hennenberg et al., 2014b), the role of Rac in the control of smooth muscle tone is just emerging. "
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    ABSTRACT: Background and purpose: Medical therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) targets smooth muscle contraction in the prostate, or prostate growth. However, current therapeutic options are insufficient. Here, we investigated the role of Rac in the control of smooth muscle tone in human prostates and growth of prostate stromal cells. Experimental approach: Experiments were performed using human prostate tissues from radical prostatectomy and cultured stromal cells (WPMY-1). Expression of Rac was examined by Western blot and fluorescence staining. Effects of Rac inhibitors (NSC23766 and EHT1864) on contractility were assessed in the organ bath. The effects of Rac inhibitors were assessed by pull-down, cytotoxicity using a cell counting kit, cytoskeletal organization by phalloidin staining and cell growth using an 5-ethynyl-2'-deoxyuridine assay. Key results: Expression of Rac1-3 was observed in prostate samples from each patient. Immunoreactivity for Rac1-3 was observed in the stroma, where it colocalized with the smooth muscle marker, calponin. NSC23766 and EHT1864 significantly reduced contractions of prostate strips induced by noradrenaline, phenylephrine or electrical field stimulation. NSC23766 and EHT1864 inhibited Rac activity in WPMY-1 cells. Survival of WPMY-1 cells ranged between 64 and 81% after incubation with NSC23766 (50 or 100 μM) or EHT1864 (25 μM) for 24 h. NSC23766 and EHT1864 induced cytoskeletal disorganization in WPMY-1 cells. Both inhibitors impaired the growth of WPMY-1 cells. Conclusions and implications: Rac may be a link connecting the control of prostate smooth muscle tone with proliferation of smooth muscle cells. Improvements in LUTS suggestive of BPH by Rac inhibitors appears possible.
    British Journal of Pharmacology 01/2015; 172(11). DOI:10.1111/bph.13099 · 4.84 Impact Factor
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