Encyclopedia of Signaling Molecules

2012 Edition
| Editors: Sangdun Choi

Ras-Related Associated with Diabetes

  • Jose-Luis González de Aguilar
Reference work entry
DOI: https://doi.org/10.1007/978-1-4419-0461-4_294

Synonyms

Historical Background

Ras associated with diabetes (Rad) was identified in the beginning of the 1990s as a clone differentially expressed in two subtraction cDNA libraries prepared from skeletal muscle of normal individuals and patients with Type II (non-insulin-dependent) diabetes mellitus (Reynet and Kahn 1993). Analysis of the newly identified clone revealed about 50% identity at the nucleotide level with members of the Ras superfamily, which consists of more than a hundred low-molecular-weight guanine nucleotide–binding proteins, also referred to as small GTPases. The major feature of this class of molecules is their ability to cycle between a GDP-bound inactive and a GTP-bound active conformation. Small GTPases are divided into six subfamilies: Ras, Rho, Arf, Rab,  Ran, and RGK, in which Rad is included. They participate in important cellular processes such as growth and differentiation, cytoskeletal dynamics, membrane...

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References

  1. Béguin P, Mahalakshmi RN, Nagashima K, Cher DH, Ikeda H, Yamada Y, et al. Nuclear sequestration of beta-subunits by Rad and Rem is controlled by 14-3-3 and calmodulin and reveals a novel mechanism for Ca2+ channel regulation. J Mol Biol. 2006;355:34–46.PubMedCrossRefGoogle Scholar
  2. Caldwell JS, Moyers JS, Doria A, Reynet C, Kahn RC. Molecular cloning of the human rad gene: gene structure and complete nucleotide sequence. Biochim Biophys Acta. 1996;1316:145–8.PubMedCrossRefGoogle Scholar
  3. Chang L, Zhang J, Tseng YH, Xie CQ, Ilany J, Brüning JC, et al. Rad GTPase deficiency leads to cardiac hypertrophy. Circulation. 2007;116:2976–83.PubMedCrossRefGoogle Scholar
  4. Finlin BS, Crump SM, Satin J, Andres DA. Regulation of voltage-gated calcium channel activity by the Rem and Rad GTPases. Proc Natl Acad Sci USA. 2003;100:14469–74.PubMedCrossRefGoogle Scholar
  5. Fu M, Zhang J, Tseng YH, Cui T, Zhu X, Xiao Y, et al. Rad GTPase attenuates vascular lesion formation by inhibition of vascular smooth muscle cell migration. Circulation. 2005;111:1071–7.PubMedCrossRefGoogle Scholar
  6. Halter B, Gonzalez de Aguilar JL, Rene F, Petri S, Fricker B, Echaniz-Laguna A, et al. Oxidative stress in skeletal muscle stimulates early expression of Rad in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med. 2010;48:915–23.PubMedCrossRefGoogle Scholar
  7. Hawke TJ, Kanatous SB, Martin CM, Goetsch SC, Garry DJ. Rad is temporally regulated within myogenic progenitor cells during skeletal muscle regeneration. Am J Physiol Cell Physiol. 2006;290:C379–87.PubMedCrossRefGoogle Scholar
  8. Hsiao BY, Chen CC, Hsieh PC, Chang TK, Yeh YC, Wu YC, et al. Rad is a p53 direct transcriptional target that inhibits cell migration and is frequently silenced in lung carcinoma cells. J Mol Med (Berl).. 2011;89:481–92.CrossRefGoogle Scholar
  9. Ilany J, Bilan PJ, Kapur S, Caldwell JS, Patti ME, Marette A, et al. Overexpression of Rad in muscle worsens diet-induced insulin resistance and glucose intolerance and lowers plasma triglyceride level. Proc Natl Acad Sci USA. 2006;103:4481–6.PubMedCrossRefGoogle Scholar
  10. Mahalakshmi RN, Ng MY, Guo K, Qi Z, Hunziker W, Béguin P. Nuclear localization of endogenous RGK proteins and modulation of cell shape remodeling by regulated nuclear transport. Traffic. 2007;8:1164–78.PubMedCrossRefGoogle Scholar
  11. Moyers JS, Bilan PJ, Reynet C, Kahn CR. Overexpression of Rad inhibits glucose uptake in cultured muscle and fat cells. J Biol Chem. 1996;271:23111–16.PubMedCrossRefGoogle Scholar
  12. Moyers JS, Zhu J, Kahn CR. Effects of phosphorylation on function of the Rad GTPase. Biochem J. 1998;333:609–14.PubMedGoogle Scholar
  13. Paulik MA, Hamacher LL, Yarnall DP, Simmons CJ, Maianu L, Pratley RE, et al. Identification of Rad’s effector-binding domain, intracellular localization, and analysis of expression in Pima Indians. J Cell Biochem. 1997;65:527–41.PubMedCrossRefGoogle Scholar
  14. Reynet C, Kahn CR. Rad: a member of the Ras family overexpressed in muscle of type II diabetic humans. Science. 1993;262:1441–4.PubMedCrossRefGoogle Scholar
  15. Sun Z, Zhang J, Zhang J, Chen C, Du Q, Chang L, et al. Rad GTPase induces cardiomyocyte apoptosis through the activation of p38 mitogen-activated protein kinase. Biochem Biophys Res Commun. 2011;409:52–7.PubMedCrossRefGoogle Scholar
  16. Suzuki M, Shigematsu H, Shames DS, Sunaga N, Takahashi T, Shivapurkar N, et al. Methylation and gene silencing of the Ras-related GTPase gene in lung and breast cancers. Ann Surg Oncol. 2007;14:1397–404.PubMedCrossRefGoogle Scholar
  17. Tseng YH, Vicent D, Zhu J, Niu Y, Adeyinka A, Moyers JS, et al. Regulation of growth and tumorigenicity of breast cancer cells by the low molecular weight GTPase Rad and nm23. Cancer Res. 2001;61:2071–9.PubMedGoogle Scholar
  18. Ward Y, Yap SF, Ravichandran V, Matsumura F, Ito M, Spinelli B, et al. The GTP binding proteins Gem and Rad are negative regulators of the Rho-Rho kinase pathway. J Cell Biol. 2002;157:291–302.PubMedCrossRefGoogle Scholar
  19. Yada H, Murata M, Shimoda K, Yuasa S, Kawaguchi H, Ieda M, et al. Dominant negative suppression of Rad leads to QT prolongation and causes ventricular arrhythmias via modulation of L-type Ca2+ channels in the heart. Circ Res. 2007;101:69–77.PubMedCrossRefGoogle Scholar
  20. Zhang J, Chang L, Chen C, Zhang M, Luo Y, Hamblin M, et al. Rad GTPase inhibits cardiac fibrosis through connective tissue growth factor. Cardiovasc Res. 2011;91:90–8.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Laboratory of Molecular Signaling and Neurodegeneration, INSERM, Faculty of Life SciencesUniversity of StrasbourgStrasbourgFrance