Skip to main content

Ral

  • Living reference work entry
  • First Online:
  • 87 Accesses

Synonyms

RAS-like protein

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...

This is a preview of subscription content, log in via an institution.

References

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Chardin P, Tavitian A. Coding sequences of human ralA and ralB cDNAs. Nucleic Acids Res. 1989;17(11):4380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Chien Y, White MA. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Rep. 2003;4(8):800–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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. doi:10.1074/jbc.M115.656710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • Park SH, Weinberg RA. A putative effector of Ral has homology to Rho/Rac GTPase activating proteins. Oncogene. 1995;11(11):2349–55.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen Y, Xu L, Foster DA. Role for phospholipase D in receptor-mediated endocytosis. Mol Cell Biol. 2001;21(2):595–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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. doi:10.1074/jbc.M116.720243.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang KL, Roufogalis BD. Ca2+/calmodulin stimulates GTP binding to the ras-related protein ral-A. J Biol Chem. 1999;274(21):14525–8.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David F. Kashatus .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media LLC

About this entry

Cite this entry

Pollock, S.R., Kashatus, D.F. (2016). Ral. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6438-9_101835-1

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-6438-9_101835-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, New York, NY

  • Online ISBN: 978-1-4614-6438-9

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics