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EMBO J. Dec 1, 1998; 17(23): 6776–6782.
PMCID: PMC1171024

All in the family? New insights and questions regarding interconnectivity of Ras, Rap1 and Ral.


Ras, Rap1 and Ral are related small GTPases. While the function of Ras in signal transduction is well established, it has been recognized only recently that Rap1 and Ral also are activated rapidly in response to a large variety of extracellular signals. Between the three GTPase an intriguing interconnectivity exists, in that guanine nucleotide exchange factors for Ral associate with the GTP-bound form of both Ras and Rap1. Furthermore, Rap1 is considered to function as an antagonist of Ras signalling by trapping Ras effectors in an inactive complex. Here, I summarize the recent developments in understanding the functional relationship between these three GTPase and argue that Rap1 functions in a signalling pathway distinct from Ras, while using similar or identical effectors.

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Selected References

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  • Altschuler D, Lapetina EG. Mutational analysis of the cAMP-dependent protein kinase-mediated phosphorylation site of Rap1b. J Biol Chem. 1993 Apr 5;268(10):7527–7531. [PubMed]
  • Altschuler DL, Ribeiro-Neto F. Mitogenic and oncogenic properties of the small G protein Rap1b. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7475–7479. [PMC free article] [PubMed]
  • Altschuler DL, Peterson SN, Ostrowski MC, Lapetina EG. Cyclic AMP-dependent activation of Rap1b. J Biol Chem. 1995 May 5;270(18):10373–10376. [PubMed]
  • Bender A. Genetic evidence for the roles of the bud-site-selection genes BUD5 and BUD2 in control of the Rsr1p (Bud1p) GTPase in yeast. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):9926–9929. [PMC free article] [PubMed]
  • Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J. The structural basis of the activation of Ras by Sos. Nature. 1998 Jul 23;394(6691):337–343. [PubMed]
  • Bos JL. ras oncogenes in human cancer: a review. Cancer Res. 1989 Sep 1;49(17):4682–4689. [PubMed]
  • Bos JL. Ras-like GTPases. Biochim Biophys Acta. 1997 Oct 24;1333(2):M19–M31. [PubMed]
  • Bos JL, Franke B, M'Rabet L, Reedquist K, Zwartkruis F. In search of a function for the Ras-like GTPase Rap1. FEBS Lett. 1997 Jun 23;410(1):59–62. [PubMed]
  • Boussiotis VA, Freeman GJ, Berezovskaya A, Barber DL, Nadler LM. Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rap1. Science. 1997 Oct 3;278(5335):124–128. [PubMed]
  • Burgering BM, Bos JL. Regulation of Ras-mediated signalling: more than one way to skin a cat. Trends Biochem Sci. 1995 Jan;20(1):18–22. [PubMed]
  • Chant J, Corrado K, Pringle JR, Herskowitz I. Yeast BUD5, encoding a putative GDP-GTP exchange factor, is necessary for bud site selection and interacts with bud formation gene BEM1. Cell. 1991 Jun 28;65(7):1213–1224. [PubMed]
  • Chenevert J, Corrado K, Bender A, Pringle J, Herskowitz I. A yeast gene (BEM1) necessary for cell polarization whose product contains two SH3 domains. Nature. 1992 Mar 5;356(6364):77–79. [PubMed]
  • Cook SJ, Rubinfeld B, Albert I, McCormick F. RapV12 antagonizes Ras-dependent activation of ERK1 and ERK2 by LPA and EGF in Rat-1 fibroblasts. EMBO J. 1993 Sep;12(9):3475–3485. [PMC free article] [PubMed]
  • D'Adamo DR, Novick S, Kahn JM, Leonardi P, Pellicer A. rsc: a novel oncogene with structural and functional homology with the gene family of exchange factors for Ral. Oncogene. 1997 Mar 20;14(11):1295–1305. [PubMed]
  • Daub H, Wallasch C, Lankenau A, Herrlich A, Ullrich A. Signal characteristics of G protein-transactivated EGF receptor. EMBO J. 1997 Dec 1;16(23):7032–7044. [PMC free article] [PubMed]
  • Ebinu JO, Bottorff DA, Chan EY, Stang SL, Dunn RJ, Stone JC. RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. Science. 1998 May 15;280(5366):1082–1086. [PubMed]
  • Fam NP, Fan WT, Wang Z, Zhang LJ, Chen H, Moran MF. Cloning and characterization of Ras-GRF2, a novel guanine nucleotide exchange factor for Ras. Mol Cell Biol. 1997 Mar;17(3):1396–1406. [PMC free article] [PubMed]
  • Farnsworth CL, Freshney NW, Rosen LB, Ghosh A, Greenberg ME, Feig LA. Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF. Nature. 1995 Aug 10;376(6540):524–527. [PubMed]
  • Feig LA, Urano T, Cantor S. Evidence for a Ras/Ral signaling cascade. Trends Biochem Sci. 1996 Nov;21(11):438–441. [PubMed]
  • Fields PE, Gajewski TF, Fitch FW. Blocked Ras activation in anergic CD4+ T cells. Science. 1996 Mar 1;271(5253):1276–1278. [PubMed]
  • Franke B, Akkerman JW, Bos JL. Rapid Ca2+-mediated activation of Rap1 in human platelets. EMBO J. 1997 Jan 15;16(2):252–259. [PMC free article] [PubMed]
  • Gotoh T, Hattori S, Nakamura S, Kitayama H, Noda M, Takai Y, Kaibuchi K, Matsui H, Hatase O, Takahashi H, et al. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G. Mol Cell Biol. 1995 Dec;15(12):6746–6753. [PMC free article] [PubMed]
  • Hariharan IK, Carthew RW, Rubin GM. The Drosophila roughened mutation: activation of a rap homolog disrupts eye development and interferes with cell determination. Cell. 1991 Nov 15;67(4):717–722. [PubMed]
  • Hofer F, Fields S, Schneider C, Martin GS. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11089–11093. [PMC free article] [PubMed]
  • Hofer F, Berdeaux R, Martin GS. Ras-independent activation of Ral by a Ca(2+)-dependent pathway. Curr Biol. 1998 Jul 2;8(14):839–842. [PubMed]
  • Ichiba T, Kuraishi Y, Sakai O, Nagata S, Groffen J, Kurata T, Hattori S, Matsuda M. Enhancement of guanine-nucleotide exchange activity of C3G for Rap1 by the expression of Crk, CrkL, and Grb2. J Biol Chem. 1997 Aug 29;272(35):22215–22220. [PubMed]
  • 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 Jan 9;273(2):814–821. [PubMed]
  • Jiang H, Luo JQ, Urano T, Frankel P, Lu Z, Foster DA, Feig LA. Involvement of Ral GTPase in v-Src-induced phospholipase D activation. Nature. 1995 Nov 23;378(6555):409–412. [PubMed]
  • Johnson L, Greenbaum D, Cichowski K, Mercer K, Murphy E, Schmitt E, Bronson RT, Umanoff H, Edelmann W, Kucherlapati R, et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 1997 Oct 1;11(19):2468–2481. [PMC free article] [PubMed]
  • Katz ME, McCormick F. Signal transduction from multiple Ras effectors. Curr Opin Genet Dev. 1997 Feb;7(1):75–79. [PubMed]
  • Khosravi-Far R, White MA, Westwick JK, Solski PA, Chrzanowska-Wodnicka M, Van Aelst L, Wigler MH, Der CJ. Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol. 1996 Jul;16(7):3923–3933. [PMC free article] [PubMed]
  • Kikuchi A, Demo SD, Ye ZH, Chen YW, Williams LT. ralGDS family members interact with the effector loop of ras p21. Mol Cell Biol. 1994 Nov;14(11):7483–7491. [PMC free article] [PubMed]
  • Kimmelman A, Tolkacheva T, Lorenzi MV, Osada M, Chan AM. Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution. Oncogene. 1997 Nov 27;15(22):2675–2685. [PubMed]
  • Kishida S, Koyama S, Matsubara K, Kishida M, Matsuura Y, Kikuchi A. Colocalization of Ras and Ral on the membrane is required for Ras-dependent Ral activation through Ral GDP dissociation stimulator. Oncogene. 1997 Dec 11;15(24):2899–2907. [PubMed]
  • Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y, Noda M. A ras-related gene with transformation suppressor activity. Cell. 1989 Jan 13;56(1):77–84. [PubMed]
  • Kiyokawa E, Mochizuki N, Kurata T, Matsuda M. Role of Crk oncogene product in physiologic signaling. Crit Rev Oncog. 1997;8(4):329–342. [PubMed]
  • Li Q, Hariharan IK, Chen F, Huang Y, Fischer JA. Genetic interactions with Rap1 and Ras1 reveal a second function for the fat facets deubiquitinating enzyme in Drosophila eye development. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12515–12520. [PMC free article] [PubMed]
  • Li W, Whaley CD, Mondino A, Mueller DL. Blocked signal transduction to the ERK and JNK protein kinases in anergic CD4+ T cells. Science. 1996 Mar 1;271(5253):1272–1276. [PubMed]
  • Lopez-Ilasaca M, Crespo P, Pellici PG, Gutkind JS, Wetzker R. Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase gamma. Science. 1997 Jan 17;275(5298):394–397. [PubMed]
  • Marshall CJ. Ras effectors. Curr Opin Cell Biol. 1996 Apr;8(2):197–204. [PubMed]
  • Matsumoto K, Asano T, Endo T. Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton. Oncogene. 1997 Nov 13;15(20):2409–2417. [PubMed]
  • McLeod SJ, Ingham RJ, Bos JL, Kurosaki T, Gold MR. Activation of the Rap1 GTPase by the B cell antigen receptor. J Biol Chem. 1998 Oct 30;273(44):29218–29223. [PubMed]
  • Michelitch M, Chant J. A mechanism of Bud1p GTPase action suggested by mutational analysis and immunolocalization. Curr Biol. 1996 Apr 1;6(4):446–454. [PubMed]
  • M'Rabet L, Coffer P, Zwartkruis F, Franke B, Segal AW, Koenderman L, Bos JL. Activation of the small GTPase rap1 in human neutrophils. Blood. 1998 Sep 15;92(6):2133–2140. [PubMed]
  • Murai H, Ikeda M, Kishida S, Ishida O, Okazaki-Kishida M, Matsuura Y, Kikuchi A. Characterization of Ral GDP dissociation stimulator-like (RGL) activities to regulate c-fos promoter and the GDP/GTP exchange of Ral. J Biol Chem. 1997 Apr 18;272(16):10483–10490. [PubMed]
  • Noda M. Structures and functions of the K rev-1 transformation suppressor gene and its relatives. Biochim Biophys Acta. 1993 May 25;1155(1):97–109. [PubMed]
  • Ohtsuka T, Shimizu K, Yamamori B, Kuroda S, Takai Y. Activation of brain B-Raf protein kinase by Rap1B small GTP-binding protein. J Biol Chem. 1996 Jan 19;271(3):1258–1261. [PubMed]
  • Okada S, Matsuda M, Anafi M, Pawson T, Pessin JE. Insulin regulates the dynamic balance between Ras and Rap1 signaling by coordinating the assembly states of the Grb2-SOS and CrkII-C3G complexes. EMBO J. 1998 May 1;17(9):2554–2565. [PMC free article] [PubMed]
  • Park HO, Chant J, Herskowitz I. BUD2 encodes a GTPase-activating protein for Bud1/Rsr1 necessary for proper bud-site selection in yeast. Nature. 1993 Sep 16;365(6443):269–274. [PubMed]
  • Park HO, Bi E, Pringle JR, Herskowitz I. Two active states of the Ras-related Bud1/Rsr1 protein bind to different effectors to determine yeast cell polarity. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4463–4468. [PMC free article] [PubMed]
  • Pizon V, Desjardins M, Bucci C, Parton RG, Zerial M. Association of Rap1a and Rap1b proteins with late endocytic/phagocytic compartments and Rap2a with the Golgi complex. J Cell Sci. 1994 Jun;107(Pt 6):1661–1670. [PubMed]
  • Pronk GJ, Bos JL. The role of p21ras in receptor tyrosine kinase signalling. Biochim Biophys Acta. 1994 Dec 30;1198(2-3):131–147. [PubMed]
  • Reedquist KA, Bos JL. Costimulation through CD28 suppresses T cell receptor-dependent activation of the Ras-like small GTPase Rap1 in human T lymphocytes. J Biol Chem. 1998 Feb 27;273(9):4944–4949. [PubMed]
  • Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J. Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J. 1996 May 15;15(10):2442–2451. [PMC free article] [PubMed]
  • Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A, Downward J. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell. 1997 May 2;89(3):457–467. [PubMed]
  • Scheffzek K, Ahmadian MR, Kabsch W, Wiesmüller L, Lautwein A, Schmitz F, Wittinghofer A. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science. 1997 Jul 18;277(5324):333–338. [PubMed]
  • Serebriiskii I, Estojak J, Sonoda G, Testa JR, Golemis EA. Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22. Oncogene. 1997 Aug 28;15(9):1043–1049. [PubMed]
  • Spaargaren M, Bischoff JR. Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12609–12613. [PMC free article] [PubMed]
  • Symons M. Rho family GTPases: the cytoskeleton and beyond. Trends Biochem Sci. 1996 May;21(5):178–181. [PubMed]
  • Urano T, Emkey R, Feig LA. Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. EMBO J. 1996 Feb 15;15(4):810–816. [PMC free article] [PubMed]
  • van Biesen T, Hawes BE, Luttrell DK, Krueger KM, Touhara K, Porfiri E, Sakaue M, Luttrell LM, Lefkowitz RJ. Receptor-tyrosine-kinase- and G beta gamma-mediated MAP kinase activation by a common signalling pathway. Nature. 1995 Aug 31;376(6543):781–784. [PubMed]
  • van den Berghe N, Cool RH, Horn G, Wittinghofer A. Biochemical characterization of C3G: an exchange factor that discriminates between Rap1 and Rap2 and is not inhibited by Rap1A(S17N). Oncogene. 1997 Aug 14;15(7):845–850. [PubMed]
  • Wang KL, Khan MT, Roufogalis BD. Identification and characterization of a calmodulin-binding domain in Ral-A, a Ras-related GTP-binding protein purified from human erythrocyte membrane. J Biol Chem. 1997 Jun 20;272(25):16002–16009. [PubMed]
  • White MA, Nicolette C, Minden A, Polverino A, Van Aelst L, Karin M, Wigler MH. Multiple Ras functions can contribute to mammalian cell transformation. Cell. 1995 Feb 24;80(4):533–541. [PubMed]
  • White MA, Vale T, Camonis JH, Schaefer E, Wigler MH. A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation. J Biol Chem. 1996 Jul 12;271(28):16439–16442. [PubMed]
  • Wittinghofer A, Nassar N. How Ras-related proteins talk to their effectors. Trends Biochem Sci. 1996 Dec;21(12):488–491. [PubMed]
  • Wolthuis RM, Bauer B, van 't Veer LJ, de Vries-Smits AM, Cool RH, Spaargaren M, Wittinghofer A, Burgering BM, Bos JL. RalGDS-like factor (Rlf) is a novel Ras and Rap 1A-associating protein. Oncogene. 1996 Jul 18;13(2):353–362. [PubMed]
  • Wolthuis RM, de Ruiter ND, Cool RH, Bos JL. Stimulation of gene induction and cell growth by the Ras effector Rlf. EMBO J. 1997 Nov 17;16(22):6748–6761. [PMC free article] [PubMed]
  • Wolthuis RM, Franke B, van Triest M, Bauer B, Cool RH, Camonis JH, Akkerman JW, Bos JL. Activation of the small GTPase Ral in platelets. Mol Cell Biol. 1998 May;18(5):2486–2491. [PMC free article] [PubMed]
  • Wolthuis RM, Zwartkruis F, Moen TC, Bos JL. Ras-dependent activation of the small GTPase Ral. Curr Biol. 1998 Apr 9;8(8):471–474. [PubMed]
  • 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 Dec 12;272(50):31230–31234. [PubMed]
  • York RD, Yao H, Dillon T, Ellig CL, Eckert SP, McCleskey EW, Stork PJ. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature. 1998 Apr 9;392(6676):622–626. [PubMed]
  • Yoshida Y, Kawata M, Miura Y, Musha T, Sasaki T, Kikuchi A, Takai Y. Microinjection of smg/rap1/Krev-1 p21 into Swiss 3T3 cells induces DNA synthesis and morphological changes. Mol Cell Biol. 1992 Aug;12(8):3407–3414. [PMC free article] [PubMed]
  • Zwartkruis FJ, Wolthuis RM, Nabben NM, Franke B, Bos JL. Extracellular signal-regulated activation of Rap1 fails to interfere in Ras effector signalling. EMBO J. 1998 Oct 15;17(20):5905–5912. [PMC free article] [PubMed]

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