Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Sarah R. Pollock
  • David F. KashatusEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101835


Historical Background

Ral proteins, RalA and RalB, are members of the Ras family of small GTPases. Ral proteins are activated by guanine nucleotide exchange factors (GEFs) that catalyze the exchange of GDP for GTP and facilitate the binding of Ral to its various downstream effector proteins. GTPase-activating proteins (GAPs) stimulate the hydrolysis of GTP to GDP, which inactivates Ral.

The discovery that many tumors contained a transforming Ras allele (HRAS, KRAS and NRAS) in the 1980s spurred interest in identifying new members of the Ras family. In 1986, Pierre Chardin and Armand Tavitian synthesized a 20-mer oligonucleotide probe corresponding to a conserved region of Ras proteins to identify novel Ras genes by screening a simian B-cell line cDNA library (Chardin and Tavitian 1986). The screen resulted in the discovery of an open reading frame that shared a high degree of homology with the three Ras genes and was consequently named Ral (Ras-like). The...

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  1. Awasthi S, Cheng J, Singhal SS, Saini MK, Pandya U, Pikula S, et al. Novel function of human RLIP76: ATP-dependent transport of glutathione conjugates and doxorubicin. Biochemistry. 2000;39(31):9327–34.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Balakireva M, Rosse C, Langevin J, Chien Y-C, Gho M, Gonzy-Treboul G, et al. The Ral/exocyst effector complex counters c-Jun N-terminal kinase-dependent apoptosis in Drosophila melanogaster. Mol Cell Biol. 2006;26(23):8953–63.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bhullar RP, Chardin P, Haslam RJ. Identification of multiple ral gene products in human platelets that account for some but not all of the platelet Gn-proteins. FEBS Lett. 1990;260(1):48–52.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bivona TG, Quatela SE, Bodemann BO, Ahearn IM, Soskis MJ, Mor A, et al. PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol Cell. 2006;21(4):481–93.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bodemann BO, Orvedahl A, Cheng T, Ram RR, Ou Y-H, Formstecher E, et al. RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell. 2011;144(2):253–67.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Campbell LJ, Peppa M, Crabtree MD, Shafiq A, McGough NF, Mott HR, et al. Thermodynamic mapping of effector protein interfaces with RalA and RalB. Biochemistry. 2015;54(6):1380–9.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Cantor SB, Urano T, Feig LA. Identification and characterization of Ral-binding protein 1, a potential downstream target of Ral GTPases. Mol Cell Biol. 1995;15(8):4578–84.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Chardin P, Tavitian A. The ral gene: a new ras related gene isolated by the use of a synthetic probe. The EMBO J. 1986;5(9):2203–8.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chardin P, Tavitian A. Coding sequences of human ralA and ralB cDNAs. Nucleic Acids Res. 1989;17(11):4380.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Chen X-W, Leto D, Chiang S-H, Wang Q, Saltiel AR. Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c. DEVCEL. 2007;13(3):391–404.Google Scholar
  11. Chen Y, Zhou Y, Qiu S, Wang K, Liu S, Peng X-X, et al. Autoantibodies to tumor-associated antigens combined with abnormal alpha-fetoprotein enhance immunodiagnosis of hepatocellular carcinoma. Cancer Lett. 2010;289(1):32–9.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Chien Y, White MA. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Rep. 2003;4(8):800–6.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Chien Y, Kim S, Bumeister R, Loo Y-M, Kwon SW, Johnson CL, et al. RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell. 2006;127(1):157–70.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Clough RR, Sidhu RS, Bhullar RP. Calmodulin binds RalA and RalB and is required for the thrombin-induced activation of Ral in human platelets. J Biol Chem. 2002;277(32):28972–80.PubMedPubMedCentralCrossRefGoogle Scholar
  15. de Gorter DJJ, Reijmers RM, Beuling EA, Naber HPH, Kuil A, Kersten MJ, et al. The small GTPase Ral mediates SDF-1-induced migration of B cells and multiple myeloma cells. Blood. 2008;111(7):3364–72.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Falsetti SC, Wang D-A, Peng H, Carrico D, Cox AD, Der CJ, et al. Geranylgeranyltransferase I inhibitors target RalB to inhibit anchorage-dependent growth and induce apoptosis and RalA to inhibit anchorage-independent growth. Mol Cell Biol. 2007;27(22):8003–14.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Frankel P, Aronheim A, Kavanagh E, Balda MS, Matter K, Bunney TD, et al. RalA interacts with ZONAB in a cell density-dependent manner and regulates its transcriptional activity. The EMBO J. 2005;24(1):54–62.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Gentry LR, Nishimura A, Cox AD, Martin TD, Tsygankov D, Nishida M, et al. Divergent roles of CAAX motif-signaled posttranslational modifications in the regulation and subcellular localization of Ral GTPases. J Biol Chem. 2015;290(37):22851–61.  https://doi.org/10.1074/jbc.M115.656710.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Ginn KF, Fangman B, Terai K, Wise A, Ziazadeh D, Shah K, et al. RalA is overactivated in medulloblastoma. J Neuro-Oncol. 2016;130(1):99–110.CrossRefGoogle Scholar
  20. Hamad NM, Elconin JH, Karnoub AE, Bai W, Rich JN, Abraham RT, et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 2002;16(16):2045–57.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Hsieh CL, Swaroop A, Francke U. Chromosomal localization and cDNA sequence of human ralB, a GTP binding protein. Somat Cell Mol Genet. 1990;16(4):407–10.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Ikeda M, Ishida O, Hinoi T, Kishida S, Kikuchi A. Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral. J Biol Chem. 1998;273(2):814–21.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Jullien-Flores V, Dorseuil O, Romero F, Letourneur F, Saragosti S, Berger R, et al. Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with CDC42/Rac GTPase-activating protein activity. J Biol Chem. 1995;270(38):22473–7.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Jullien-Flores V, Mahé Y, Mirey G, Leprince C, Meunier-Bisceuil B, Sorkin A, et al. RLIP76, an effector of the GTPase Ral, interacts with the AP2 complex: involvement of the Ral pathway in receptor endocytosis. J Cell Sci. 2000;113(Pt 16):2837–44.PubMedPubMedCentralGoogle Scholar
  25. Kashatus DF, Lim K-H, Brady DC, Pershing NLK, Cox AD, Counter CM. RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat Cell Biol. 2011;13(8):1–10.Google Scholar
  26. Kinsella BT, Erdman RA, Maltese WA. Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins encoded by rac1, rac2, and ralA. J Biol Chem. 1991;266(15):9786–94.PubMedPubMedCentralGoogle Scholar
  27. Leung KF, Baron R, Ali BR, Magee AI, Seabra MC. Rab GTPases containing a CAAX motif are processed post-geranylgeranylation by proteolysis and methylation. J Biol Chem. 2007;282(2):1487–97.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Li J, Dai L, Lei N, Xing M, Li P, Luo C, et al. Evaluation and characterization of anti-RalA autoantibody as a potential serum biomarker in human prostate cancer. Oncotarget. 2016;7(28):43546–43556.Google Scholar
  29. Lim K-H, Baines AT, Fiordalisi JJ, Shipitsin M, Feig LA, Cox AD, et al. Activation of RalA is critical for Ras-induced tumorigenesis of human cells. Cancer Cell. 2005;7(6):533–45.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Lim K-H, O'Hayer K, Adam SJ, Kendall SD, Campbell PM, Der CJ, et al. Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells. Curr Biol. 2006;16(24):2385–94.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Luo JQ, Liu X, Frankel P, Rotunda T, Ramos M, Flom J, et al. Functional association between Arf and RalA in active phospholipase D complex. Proc Natl Acad Sci USA. 1998;95(7):3632–7.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Martin TD, Samuel JC, Routh ED, Der CJ, Yeh JJ. Activation and involvement of Ral GTPases in colorectal cancer. Cancer Res. 2011;71(1):206–15.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Martin TD, Mitin N, Cox AD, Yeh JJ, Der CJ. Phosphorylation by protein kinase Cα regulates RalB small GTPase protein activation, subcellular localization, and effector utilization. J Biol Chem. 2012;287(18):14827–36.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Mirey G, Balakireva M, L'Hoste S, Rosse C, Voegeling S, Camonis J. A Ral guanine exchange factor-Ral pathway is conserved in Drosophila melanogaster and sheds new light on the connectivity of the Ral, Ras, and Rap pathways. Mol Cell Biol. 2003;23(3):1112–24.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Moskalenko S, Henry DO, Rosse C, Mirey G, Camonis JH, White MA. The exocyst is a Ral effector complex. Nat Cell. 2002;4(1):66–72.CrossRefGoogle Scholar
  36. Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, et al. Ral GTPases regulate exocyst assembly through dual subunit interactions. J Biol Chem. 2003;278(51):51743–8.PubMedCrossRefGoogle Scholar
  37. Nakashima S, Morinaka K, Koyama S, Ikeda M, Kishida M, Okawa K, et al. Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors. The EMBO Journal EMBO Press. 1999;18(13):3629–42.CrossRefGoogle Scholar
  38. Neyraud V, Aushev VN, Hatzoglou A, Meunier B, Cascone I, Camonis J. RalA and RalB proteins are ubiquitinated GTPases, and ubiquitinated RalA increases lipid raft exposure at the plasma membrane. J Biol Chem. 2012;287(35):29397–405.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Nishimura A, Linder ME. Identification of a novel prenyl and palmitoyl modification at the CaaX motif of Cdc42 that regulates RhoGDI binding. Mol Cell Biol. 2013;33(7):1417–29.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Ohta Y, Suzuki N, Nakamura S, Hartwig JH, Stossel TP. The small GTPase RalA targets filamin to induce filopodia. Proc Natl Acad Sci USA. 1999;96(5):2122–8.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Olofsson B, Chardin P, Touchot N, Zahraoui A, Tavitian A. Expression of the ras-related ralA, rho12 and rab genes in adult mouse tissues. Oncogene. 1988;3(2):231–4.PubMedPubMedCentralGoogle Scholar
  42. Park SH, Weinberg RA. A putative effector of Ral has homology to Rho/Rac GTPase activating proteins. Oncogene. 1995;11(11):2349–55.PubMedPubMedCentralGoogle Scholar
  43. Peschard P, McCarthy A, Leblanc-Dominguez V, Yeo M, Guichard S, Stamp G, et al. Genetic deletion of RALA and RALB small GTPases reveals redundant functions in development and tumorigenesis. Curr Biol. 2012;22(21):2063–8.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Sablina AA, Chen W, Arroyo JD, Corral L, Hector M, Bulmer SE, et al. The tumor suppressor PP2A Abeta regulates the RalA GTPase. Cell. 2007;129(5):969–82.PubMedPubMedCentralCrossRefGoogle Scholar
  45. Sánchez-Ruiz J, Mejías R, García-Belando M, Barber DF, González-García A. Ral GTPases regulate cell-mediated cytotoxicity in NK cells. J Immunol. 2011;187(5):2433–41.PubMedPubMedCentralCrossRefGoogle Scholar
  46. Sawamoto K, Winge P, Koyama S, Hirota Y, Yamada C, Miyao S, et al. The drosophila Ral GTPase regulates developmental cell shape changes through the Jun NH(2)-terminal kinase pathway. J Cell Biol. 1999;146(2):361–72.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Shen Y, Xu L, Foster DA. Role for phospholipase D in receptor-mediated endocytosis. Mol Cell Biol. 2001;21(2):595–602.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Shipitsin M, Feig LA. RalA but not RalB enhances polarized delivery of membrane proteins to the basolateral surface of epithelial cells. Mol Cell Biol. 2004;24(13):5746–56.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Shirai Y, Morioka S, Sakuma M, Yoshino K-I, Otsuji C, Sakai N, et al. Direct binding of RalA to PKCη and its crucial role in morphological change during keratinocyte differentiation. Mol Biol Cell. 2011;22(8):1340–52.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Sidhu RS, Elsaraj SM, Grujic O, Bhullar RP. Calmodulin binding to the small GTPase Ral requires isoprenylated Ral. Biochem Biophys Res Commun. 2005;336(1):105–9.PubMedPubMedCentralCrossRefGoogle Scholar
  51. Simicek M, Lievens S, Laga M, Guzenko D, Aushev VN, Kalev P, et al. The deubiquitylase USP33 discriminates between RALB functions in autophagy and innate immune response. Nat Cell Biol. 2013;15(10):1220–30.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Smith SC, Oxford G, Baras AS, Owens C, Havaleshko D, Brautigan DL, et al. Expression of ral GTPases, their effectors, and activators in human bladder cancer. Clin Cancer Res. 2007;13(13):3803–13.PubMedPubMedCentralCrossRefGoogle Scholar
  53. Song X, Hua L, Xu Y, Fang Z, Wang Y, Gao J, et al. Involvement of RalB in the effect of geranylgeranyltransferase I on glioma cell migration and invasion. Clin Transl Oncol. 2015;17(6):477–85.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Thomas JC, Cooper JM, Clayton NS, Wang C, White MA, Abell C, et al. Inhibition of Ral GTPases using a stapled peptide approach. J Biol Chem. 2016;291:18310–25.  https://doi.org/10.1074/jbc.M116.720243.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Vitale N, Chasserot-Golaz S, Bailly Y, Morinaga N, Frohman MA, Bader M-F. Calcium-regulated exocytosis of dense-core vesicles requires the activation of ADP-ribosylation factor (ARF)6 by ARF nucleotide binding site opener at the plasma membrane. J Cell Biol. 2002;159(1):79–89.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Wang KL, Roufogalis BD. Ca2+/calmodulin stimulates GTP binding to the ras-related protein ral-A. J Biol Chem. 1999;274(21):14525–8.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Wang H, Owens C, Chandra N, Conaway MR, Brautigan DL, Theodorescu D. Phosphorylation of RalB is important for bladder cancer cell growth and metastasis. Cancer Res. 2010;70(21):8760–9.PubMedPubMedCentralCrossRefGoogle Scholar
  58. Wildey GM, Viggeswarapu M, Rim S, Denker JK. Isolation of cDNA clones and tissue expression of rat ral A and ral B GTP-binding proteins. Biochem Biophys Res Commun. 1993;194(1):552–9.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Wolthuis RM, Franke B, van Triest M, Bauer B, Cool RH, Camonis JH, et al. Activation of the small GTPase Ral in platelets. Mol Cell Biol. 1998;18(5):2486–91.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Wu J-C, Chen T-Y, Yu C-TR, Tsai S-J, Hsu J-M, Tang M-J, et al. Identification of V23RalA-Ser194 as a critical mediator for Aurora-A-induced cellular motility and transformation by small pool expression screening. J Biol Chem. 2005;280(10):9013–22.PubMedPubMedCentralCrossRefGoogle Scholar
  61. Yamaguchi A, Urano T, Goi T, Feig LA. An Eps homology (EH) domain protein that binds to the Ral-GTPase target, RalBP1. J Biol Chem. 1997;272(50):31230–4.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Yin J, Pollock C, Tracy K, Chock M, Martin P, Oberst M, et al. Activation of the RalGEF/Ral pathway promotes prostate cancer metastasis to bone. Mol Cell Biol. 2007;27(21):7538–50.PubMedPubMedCentralCrossRefGoogle Scholar
  63. Zhao Z, Rivkees SA. Tissue-specific expression of GTPas RalA and RalB during embryogenesis and regulation by epithelial-mesenchymal interaction. Mech Dev. 2000;97(1–2):201–4.PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Microbiology, Immunology and Cancer BiologyUniversity of Virginia School of MedicineCharlottesvilleUSA