Genomes and Genes
monomeric gtp binding proteins
Summary: A class of monomeric, low molecular weight (20-25 kDa) GTP-binding proteins that regulate a variety of intracellular processes. The GTP bound form of the protein is active and limited by its inherent GTPase activity, which is controlled by an array of GTPase activators, GDP dissociation inhibitors, and guanine nucleotide exchange factors. This enzyme was formerly listed as EC 220.127.116.11
- Runz H, Miura K, Weiss M, Pepperkok R. Sterols regulate ER-export dynamics of secretory cargo protein ts-O45-G. EMBO J. 2006;25:2953-65 pubmed..Consistent with this, membrane turnover of the COPII component Sec23p is delayed in sterol-depleted cells. Altogether, our results demonstrate the importance of sterol levels in COPII mediated ER-export...
- Li Y, Wang Y, Kim E, Beemiller P, Wang C, Swanson J, et al. Bnip3 mediates the hypoxia-induced inhibition on mammalian target of rapamycin by interacting with Rheb. J Biol Chem. 2007;282:35803-13 pubmed..Moreover, Bnip3 inhibits cell growth in vivo by suppressing the mTOR pathway. These observations demonstrate that Bnip3 mediates the inhibition of the mTOR pathway in response to hypoxia. ..
- Nardella C, Chen Z, Salmena L, Carracedo A, Alimonti A, Egia A, et al. Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events. Genes Dev. 2008;22:2172-7 pubmed publisher..Importantly, we show that Pten haploinsufficiency cooperates with Rheb overexpression to markedly promote prostate tumorigenesis. We conclude that Rheb acts as a proto-oncogene in the appropriate genetic milieu and signaling context. ..
- Zhang T, Li S, Zhang Y, Zhong C, Lai Z, Ding J. Crystal structure of the ARL2-GTP-BART complex reveals a novel recognition and binding mode of small GTPase with effector. Structure. 2009;17:602-10 pubmed publisher..This novel recognition and binding mode is different from that of other small GTPase-effector interactions and provides molecular basis for the high specificity of ARL2 for BART. ..
- Sherwood V, Manbodh R, Sheppard C, Chalmers A. RASSF7 is a member of a new family of RAS association domain-containing proteins and is required for completing mitosis. Mol Biol Cell. 2008;19:1772-82 pubmed publisher..Thus RASSF7, the first member of the N-terminal RASSF family to be functionally analyzed, is a centrosome-associated protein required to form a spindle and complete mitosis in the neural tube. ..
- Huang J, Manning B. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008;412:179-90 pubmed publisher..In the present review we focus on the molecular details of TSC1-TSC2 complex regulation and function as it relates to the control of Rheb and mTORC1. ..
- Yang Q, Inoki K, Kim E, Guan K. TSC1/TSC2 and Rheb have different effects on TORC1 and TORC2 activity. Proc Natl Acad Sci U S A. 2006;103:6811-6 pubmed..Our observations suggest that TSC1/2 and Rheb have different effects on the activity of TORC1 and -2, further supporting the complexity of TOR regulation. ..
- Yogi A, Callera G, Montezano A, Aranha A, Tostes R, Schiffrin E, et al. Endothelin-1, but not Ang II, activates MAP kinases through c-Src independent Ras-Raf dependent pathways in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2007;27:1960-7 pubmed..These findings suggest that Ang II and ET-1 can activate similar signaling pathways through unrelated mechanisms. MAP kinases are an important point of convergence for Ang II and ET-1. ..
- Shah O, Hunter T. Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis. Mol Cell Biol. 2006;26:6425-34 pubmed
- ten Klooster J, Hordijk P. Targeting and localized signalling by small GTPases. Biol Cell. 2007;99:1-12 pubmed..Here, local GTPase activation occurs, leading to subsequent exposure of the effector domain, binding to effector proteins and the initiation of downstream signalling. ..
- Sato T, Umetsu A, Tamanoi F. Characterization of the Rheb-mTOR signaling pathway in mammalian cells: constitutive active mutants of Rheb and mTOR. Methods Enzymol. 2008;438:307-20 pubmed publisher..We also describe a protocol for rapamycin treatment, which directly inhibits mTOR and can be used to investigate the mTOR signaling pathway in cell growth, cell size, etc. ..
- Ma D, Bai X, Guo S, Jiang Y. The switch I region of Rheb is critical for its interaction with FKBP38. J Biol Chem. 2008;283:25963-70 pubmed publisher..Our findings suggest that FKBP38 is a bona fide effector of Rheb and that the ability to interact with FKBP38 is important for Rheb as an activator of mTOR. ..
- Dale R, Gornall H, Singh Grewal D, Alcausin M, Rice G, Crow Y. Familial Aicardi-Goutières syndrome due to SAMHD1 mutations is associated with chronic arthropathy and contractures. Am J Med Genet A. 2010;152A:938-42 pubmed publisher..We propose that arthropathy with progressive contractures should now be considered part of the spectrum of Aicardi-Goutières syndrome because of SAMHD1 mutations. ..
- Ghosh S, Tergaonkar V, Rothlin C, Correa R, Bottero V, Bist P, et al. Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival. Cancer Cell. 2006;10:215-26 pubmed..These results provide evidence for a crosstalk between the TSC/Rheb/mTOR pathway and the NF-kappaB induction pathways and indicate that NF-kappaB functions as an important survival factor that regulates TSC2-dependent cell survival. ..
- Jung Y, Agrawal G, Rakwal R, Kim J, Lee M, Choi P, et al. Functional characterization of OsRacB GTPase--a potentially negative regulator of basal disease resistance in rice. Plant Physiol Biochem. 2006;44:68-77 pubmed..Based on these results, we suggest that OsRacB functions as a potential regulator for a basal disease resistance pathway in rice. ..
- Moshnikova A, Frye J, Shay J, Minna J, Khokhlatchev A. The growth and tumor suppressor NORE1A is a cytoskeletal protein that suppresses growth by inhibition of the ERK pathway. J Biol Chem. 2006;281:8143-52 pubmed..Our studies suggest that association of NORE1A with cytoskeletal elements is essential for NORE1A-induced growth suppression and that the ERK pathway is a target for NORE1A growth-suppressive activities. ..
- Ma D, Bai X, Zou H, Lai Y, Jiang Y. Rheb GTPase controls apoptosis by regulating interaction of FKBP38 with Bcl-2 and Bcl-XL. J Biol Chem. 2010;285:8621-7 pubmed publisher..Consequently, when Rheb activity increases, cells become more resistant to apoptotic inducers. Our findings reveal a novel mechanism through which growth factors and amino acids control apoptosis. ..
- Sato T, Nakashima A, Guo L, Tamanoi F. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J Biol Chem. 2009;284:12783-91 pubmed publisher..Rheb does not induce autophosphorylation of mTOR. These results suggest that Rheb induces alteration in the binding of 4E-BP1 with mTORC1 to regulate mTORC1 activation. ..
- Li Y, Werner H, Püschel A. Rheb and mTOR regulate neuronal polarity through Rap1B. J Biol Chem. 2008;283:33784-92 pubmed publisher..These results indicate that the mTOR pathway is required to counteract the Smurf2-initiated degradation of Rap1B during the establishment of neuronal polarity. ..
- Mavrakis K, Zhu H, Silva R, Mills J, Teruya Feldstein J, Lowe S, et al. Tumorigenic activity and therapeutic inhibition of Rheb GTPase. Genes Dev. 2008;22:2178-88 pubmed publisher..Of these, only eIF4E was able to enhance lymphomagenesis in vivo. In summary, the Rheb GTPase is an oncogenic activity upstream of mTORC1 and eIF4E and a direct therapeutic target of farnesyltransferase inhibitors in cancer. ..
- Samaj J, Muller J, Beck M, Böhm N, Menzel D. Vesicular trafficking, cytoskeleton and signalling in root hairs and pollen tubes. Trends Plant Sci. 2006;11:594-600 pubmed..The TGN is thought to serve the function of an early endosome in plants because it is involved in early endocytosis and rapid vesicular recycling of the plasma membrane in root epidermal cells. ..
- Kim E, Goraksha Hicks P, Li L, Neufeld T, Guan K. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008;10:935-45 pubmed publisher..Genetic studies in Drosophila also show that Rag GTPases regulate cell growth, autophagy and animal viability during starvation. Our studies establish a function of Rag GTPases in TORC1 activation in response to amino acid signals. ..
- Monje Casas F, Amon A. Cell polarity determinants establish asymmetry in MEN signaling. Dev Cell. 2009;16:132-45 pubmed publisher..Our results indicate that mother-daughter cell asymmetry determinants establish MEN signaling asymmetry through microtubule-bud cortex interactions. ..
- Jiang H, Vogt P. Constitutively active Rheb induces oncogenic transformation. Oncogene. 2008;27:5729-40 pubmed publisher..An engineered N-terminal myristylation signal can substitute for the farnesylation. Immunofluorescence localizes wild-type and mutant Rheb to vesicular structures in the cytoplasm, overlapping with the endoplasmic reticulum. ..
- Bi X, Mancias J, Goldberg J. Insights into COPII coat nucleation from the structure of Sec23.Sar1 complexed with the active fragment of Sec31. Dev Cell. 2007;13:635-45 pubmed..Substitution of the corresponding residue F382L in human Sec23A causes cranio-lenticulo-sutural dysplasia, and we suggest that this mutation disrupts the nucleation of COPII coat proteins at endoplasmic reticulum exit sites...
- Fraschini R, D Ambrosio C, Venturetti M, Lucchini G, Piatti S. Disappearance of the budding yeast Bub2-Bfa1 complex from the mother-bound spindle pole contributes to mitotic exit. J Cell Biol. 2006;172:335-46 pubmed..Moreover, it correlates with the passage of one spindle pole through the bud neck because it needs septin ring formation and bud neck kinases. ..
- Aridor M, Fish K. Selective targeting of ER exit sites supports axon development. Traffic. 2009;10:1669-84 pubmed publisher..Furthermore, axons, such as dendrites, rely on ERES targeting and assembly for growth. ..
- Fromme J, Ravazzola M, Hamamoto S, Al Balwi M, Eyaid W, Boyadjiev S, et al. The genetic basis of a craniofacial disease provides insight into COPII coat assembly. Dev Cell. 2007;13:623-34 pubmed..Our results indicate that the Sar1-Sec23-Sec24 prebudding complex is sufficient to form cargo-containing tubules in vivo, whereas the Sec13-Sec31 complex is required for membrane fission...
- Maehama T, Tanaka M, Nishina H, Murakami M, Kanaho Y, Hanada K. RalA functions as an indispensable signal mediator for the nutrient-sensing system. J Biol Chem. 2008;283:35053-9 pubmed publisher..These results collectively suggest that RalGDS and RalA act downstream of Rheb and that RalA activation is a crucial step in nutrient-induced mTORC1 activation. ..
- Bai X, Ma D, Liu A, Shen X, Wang Q, Liu Y, et al. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science. 2007;318:977-80 pubmed..Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability. ..
- Park H, Bi E. Central roles of small GTPases in the development of cell polarity in yeast and beyond. Microbiol Mol Biol Rev. 2007;71:48-96 pubmed..In this review, we discuss the key signaling pathways that regulate cell polarization during the mitotic cell cycle and during mating. ..
- Santarius M, Lee C, Anderson R. Supervised membrane swimming: small G-protein lifeguards regulate PIPK signalling and monitor intracellular PtdIns(4,5)P2 pools. Biochem J. 2006;398:1-13 pubmed..We also describe the spatial and temporal cross-regulation of PIPKs and small G-proteins that is critical for a number of cellular functions. ..
- Gillingham A, Munro S. The small G proteins of the Arf family and their regulators. Annu Rev Cell Dev Biol. 2007;23:579-611 pubmed..Here we review what is known about all the members of the Arf family, along with the known regulatory molecules that convert them between GDP- and GTP-bound states. ..
- Ramantani G, Kohlhase J, Hertzberg C, Innes A, Engel K, Hunger S, et al. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutières syndrome. Arthritis Rheum. 2010;62:1469-77 pubmed publisher..In this study we further characterized the phenotypic spectrum of this disease...
- Rice G, Bond J, Asipu A, Brunette R, Manfield I, Carr I, et al. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009;41:829-32 pubmed publisher..Here we describe mutations in SAMHD1 as the cause of AGS at the AGS5 locus and present data to show that SAMHD1 may act as a negative regulator of the cell-intrinsic antiviral response. ..
- Gao M, Kaiser C. A conserved GTPase-containing complex is required for intracellular sorting of the general amino-acid permease in yeast. Nat Cell Biol. 2006;8:657-67 pubmed..Together, these studies provide evidence that the GSE complex has a key role in trafficking Gap1p out of the endosome and may serve as coat proteins in this process. ..
- Sancak Y, Peterson T, Shaul Y, Lindquist R, Thoreen C, Bar Peled L, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008;320:1496-501 pubmed publisher..The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb. ..
- Karbowniczek M, Robertson G, Henske E. Rheb inhibits C-raf activity and B-raf/C-raf heterodimerization. J Biol Chem. 2006;281:25447-56 pubmed..In addition, we found that Rheb inhibits the association of B-Raf with H-Ras. Taken together, these results support a central role of Rheb in the regulation of the Ras/B-Raf/C-Raf/MEK signaling network. ..
- Latijnhouwers M, Hawes C, Carvalho C, Oparka K, Gillingham A, Boevink P. An Arabidopsis GRIP domain protein locates to the trans-Golgi and binds the small GTPase ARL1. Plant J. 2005;44:459-70 pubmed..This indicates that AtGRIP and AtARL1 interact directly. We conclude that the pathway involving ARL1 and GRIP domain golgins is conserved in plants. ..
- Lee M, Orci L, Hamamoto S, Futai E, Ravazzola M, Schekman R. Sar1p N-terminal helix initiates membrane curvature and completes the fission of a COPII vesicle. Cell. 2005;122:605-17 pubmed..Thus, the initiation of vesicle budding by Sar1p couples the generation of membrane curvature with coat-protein assembly and cargo capture...
- Nobukuni T, Joaquin M, Roccio M, Dann S, Kim S, Gulati P, et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci U S A. 2005;102:14238-43 pubmed
- Takahashi K, Nakagawa M, Young S, Yamanaka S. Differential membrane localization of ERas and Rheb, two Ras-related proteins involved in the phosphatidylinositol 3-kinase/mTOR pathway. J Biol Chem. 2005;280:32768-74 pubmed..Rheb also shares the same membrane-targeting pathway but because of the absence of palmitoylation is located on endomembranes. ..
- Jiang S, Ramachandran S. Comparative and evolutionary analysis of genes encoding small GTPases and their activating proteins in eukaryotic genomes. Physiol Genomics. 2006;24:235-51 pubmed
- Basso A, Mirza A, Liu G, Long B, Bishop W, Kirschmeier P. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J Biol Chem. 2005;280:31101-8 pubmed..These studies demonstrated that Rheb is modified by farnesylation, is not a substrate for alternative prenylation, and plays a role in SCH66336 enhancement of the anti-tumor response to other chemotherapeutics. ..
- Long X, Ortiz Vega S, Lin Y, Avruch J. Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency. J Biol Chem. 2005;280:23433-6 pubmed..Amino acid withdrawal may generate an inhibitor of the Rheb-mTOR interaction that interferes with the signaling function of TOR complex 1. ..
- Bielli A, Haney C, Gabreski G, Watkins S, Bannykh S, Aridor M. Regulation of Sar1 NH2 terminus by GTP binding and hydrolysis promotes membrane deformation to control COPII vesicle fission. J Cell Biol. 2005;171:919-24 pubmed..Thus Sar1-mediated GTP binding and hydrolysis regulates the NH2-terminal tail to perturb membrane packing, promote membrane deformation, and control vesicle fission...
- Tereshina M, Zaraisky A, Novoselov V. Ras-dva, a member of novel family of small GTPases, is required for the anterior ectoderm patterning in the Xenopus laevis embryo. Development. 2006;133:485-94 pubmed publisher..Together, the data obtained indicate that Ras-dva is an essential component of the signaling network that patterns the early anterior neural plate and the adjacent ectoderm in the Xenopus laevis embryos...
- Saito K, Araki Y, Kontani K, Nishina H, Katada T. Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. J Biochem. 2005;137:423-30 pubmed..The physiological roles of the two Rheb-dependent signaling pathways are discussed in terms of nutrient uptake and cell growth or cell cycle progression. ..