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PMID: 9843482 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Review

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

The EMBO journal ·Vol. 17 ·No. 23 ·1998-12-01 ·Pages 6776-82

Bos JL

Abstract

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.

MeSH Terms
Amino Acid Sequence Animals GTP-Binding Proteins/metabolism Humans Molecular Sequence Data Signal Transduction ral GTP-Binding Proteins rap GTP-Binding Proteins ras Proteins/metabolism
Chemicals
GTP-Binding Proteins ral GTP-Binding Proteins rap GTP-Binding Proteins ras Proteins
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Bos J L
Laboratory for Physiological Chemistry and Center for Biomedical Genetics, Utrecht University, Universiteitsweg 100 3584 CG Utrecht, The Netherlands. [email protected]
References (74)
74 references, click to expand
  1. K-ras is an essential gene in the mouse with partial functional overlap with N-ras.
    Genes Dev. 1997 Oct 1;11(19):2468-81 PMID: 9334313
  2. 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):12515-20 PMID: 9356481
  3. Stimulation of gene induction and cell growth by the Ras effector Rlf.
    EMBO J. 1997 Nov 17;16(22):6748-61 PMID: 9362489
  4. Signal characteristics of G protein-transactivated EGF receptor.
    EMBO J. 1997 Dec 1;16(23):7032-44 PMID: 9384582
  5. Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton.
    Oncogene. 1997 Nov 13;15(20):2409-17 PMID: 9395237
  6. Ras-like GTPases.
    Biochim Biophys Acta. 1997 Oct 24;1333(2):M19-31 PMID: 9395281
  7. An Eps homology (EH) domain protein that binds to the Ral-GTPase target, RalBP1.
    J Biol Chem. 1997 Dec 12;272(50):31230-4 PMID: 9395447
  8. 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):2675-85 PMID: 9400994
  9. 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):2899-907 PMID: 9416833
  10. 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):814-21 PMID: 9422736
  11. Blocked Ras activation in anergic CD4+ T cells.
    Science. 1996 Mar 1;271(5253):1276-8 PMID: 8638108
  12. Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation.
    Mol Cell Biol. 1996 Jul;16(7):3923-33 PMID: 8668210
  13. A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation.
    J Biol Chem. 1996 Jul 12;271(28):16439-42 PMID: 8663585
  14. A mechanism of Bud1p GTPase action suggested by mutational analysis and immunolocalization.
    Curr Biol. 1996 Apr 1;6(4):446-54 PMID: 8723349
  15. RalGDS-like factor (Rlf) is a novel Ras and Rap 1A-associating protein.
    Oncogene. 1996 Jul 18;13(2):353-62 PMID: 8710374
  16. Ras effectors.
    Curr Opin Cell Biol. 1996 Apr;8(2):197-204 PMID: 8791426
  17. Rho family GTPases: the cytoskeleton and beyond.
    Trends Biochem Sci. 1996 May;21(5):178-81 PMID: 8871402
  18. Evidence for a Ras/Ral signaling cascade.
    Trends Biochem Sci. 1996 Nov;21(11):438-41 PMID: 8987400
  19. Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase gamma.
    Science. 1997 Jan 17;275(5298):394-7 PMID: 8994038
  20. How Ras-related proteins talk to their effectors.
    Trends Biochem Sci. 1996 Dec;21(12):488-91 PMID: 9009833
  21. A ras-related gene with transformation suppressor activity.
    Cell. 1989 Jan 13;56(1):77-84 PMID: 2642744
  22. ras oncogenes in human cancer: a review.
    Cancer Res. 1989 Sep 1;49(17):4682-9 PMID: 2547513
  23. 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):1213-24 PMID: 1905981
  24. The Drosophila roughened mutation: activation of a rap homolog disrupts eye development and interferes with cell determination.
    Cell. 1991 Nov 15;67(4):717-22 PMID: 1934069
  25. A yeast gene (BEM1) necessary for cell polarization whose product contains two SH3 domains.
    Nature. 1992 Mar 5;356(6364):77-9 PMID: 1538785
  26. Microinjection of smg/rap1/Krev-1 p21 into Swiss 3T3 cells induces DNA synthesis and morphological changes.
    Mol Cell Biol. 1992 Aug;12(8):3407-14 PMID: 1321333
  27. Mutational analysis of the cAMP-dependent protein kinase-mediated phosphorylation site of Rap1b.
    J Biol Chem. 1993 Apr 5;268(10):7527-31 PMID: 8463283
  28. Structures and functions of the K rev-1 transformation suppressor gene and its relatives.
    Biochim Biophys Acta. 1993 May 25;1155(1):97-109 PMID: 8504133
  29. BUD2 encodes a GTPase-activating protein for Bud1/Rsr1 necessary for proper bud-site selection in yeast.
    Nature. 1993 Sep 16;365(6443):269-74 PMID: 8371782
  30. 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):9926-9 PMID: 8234337
  31. RapV12 antagonizes Ras-dependent activation of ERK1 and ERK2 by LPA and EGF in Rat-1 fibroblasts.
    EMBO J. 1993 Sep;12(9):3475-85 PMID: 8253074
  32. ralGDS family members interact with the effector loop of ras p21.
    Mol Cell Biol. 1994 Nov;14(11):7483-91 PMID: 7935463
  33. 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):1661-70 PMID: 7962206
  34. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator.
    Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11089-93 PMID: 7972015
  35. 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):12609-13 PMID: 7809086
  36. The role of p21ras in receptor tyrosine kinase signalling.
    Biochim Biophys Acta. 1994 Dec 30;1198(2-3):131-47 PMID: 7819271
  37. Multiple Ras functions can contribute to mammalian cell transformation.
    Cell. 1995 Feb 24;80(4):533-41 PMID: 7867061
  38. Regulation of Ras-mediated signalling: more than one way to skin a cat.
    Trends Biochem Sci. 1995 Jan;20(1):18-22 PMID: 7878738
  39. Cyclic AMP-dependent activation of Rap1b.
    J Biol Chem. 1995 May 5;270(18):10373-6 PMID: 7737967
  40. Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF.
    Nature. 1995 Aug 10;376(6540):524-7 PMID: 7637786
  41. Receptor-tyrosine-kinase- and G beta gamma-mediated MAP kinase activation by a common signalling pathway.
    Nature. 1995 Aug 31;376(6543):781-4 PMID: 7651538
  42. Identification of Rap1 as a target for the Crk SH3 domain-binding guanine nucleotide-releasing factor C3G.
    Mol Cell Biol. 1995 Dec;15(12):6746-53 PMID: 8524240
  43. Involvement of Ral GTPase in v-Src-induced phospholipase D activation.
    Nature. 1995 Nov 23;378(6555):409-12 PMID: 7477381
  44. 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):4944-9 PMID: 9478939
  45. Ras-dependent activation of the small GTPase Ral.
    Curr Biol. 1998 Apr 9;8(8):471-4 PMID: 9550702
  46. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor.
    Nature. 1998 Apr 9;392(6676):622-6 PMID: 9560161
  47. Activation of the small GTPase Ral in platelets.
    Mol Cell Biol. 1998 May;18(5):2486-91 PMID: 9566869
  48. 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):2554-65 PMID: 9564038
  49. RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs.
    Science. 1998 May 15;280(5366):1082-6 PMID: 9582122
  50. Role of Crk oncogene product in physiologic signaling.
    Crit Rev Oncog. 1997;8(4):329-42 PMID: 9622053
  51. Mitogenic and oncogenic properties of the small G protein Rap1b.
    Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7475-9 PMID: 9636174
  52. Ras-independent activation of Ral by a Ca(2+)-dependent pathway.
    Curr Biol. 1998 Jul 2;8(14):839-42 PMID: 9663394
  53. The structural basis of the activation of Ras by Sos.
    Nature. 1998 Jul 23;394(6691):337-43 PMID: 9690470
  54. Activation of the small GTPase rap1 in human neutrophils.
    Blood. 1998 Sep 15;92(6):2133-40 PMID: 9731072
  55. Extracellular signal-regulated activation of Rap1 fails to interfere in Ras effector signalling.
    EMBO J. 1998 Oct 15;17(20):5905-12 PMID: 9774335
  56. Activation of the Rap1 GTPase by the B cell antigen receptor.
    J Biol Chem. 1998 Oct 30;273(44):29218-23 PMID: 9786933
  57. Activation of brain B-Raf protein kinase by Rap1B small GTP-binding protein.
    J Biol Chem. 1996 Jan 19;271(3):1258-61 PMID: 8576107
  58. Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation.
    EMBO J. 1996 Feb 15;15(4):810-6 PMID: 8631302
  59. Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation.
    EMBO J. 1996 May 15;15(10):2442-51 PMID: 8665852
  60. Blocked signal transduction to the ERK and JNK protein kinases in anergic CD4+ T cells.
    Science. 1996 Mar 1;271(5253):1272-6 PMID: 8638107
  61. Signal transduction from multiple Ras effectors.
    Curr Opin Genet Dev. 1997 Feb;7(1):75-9 PMID: 9024640
  62. Rapid Ca2+-mediated activation of Rap1 in human platelets.
    EMBO J. 1997 Jan 15;16(2):252-9 PMID: 9029146
  63. Cloning and characterization of Ras-GRF2, a novel guanine nucleotide exchange factor for Ras.
    Mol Cell Biol. 1997 Mar;17(3):1396-406 PMID: 9032266
  64. 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):10483-90 PMID: 9099691
  65. 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):4463-8 PMID: 9114012
  66. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras.
    Cell. 1997 May 2;89(3):457-67 PMID: 9150145
  67. rsc: a novel oncogene with structural and functional homology with the gene family of exchange factors for Ral.
    Oncogene. 1997 Mar 20;14(11):1295-305 PMID: 9178890
  68. 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):16002-9 PMID: 9188503
  69. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants.
    Science. 1997 Jul 18;277(5324):333-8 PMID: 9219684
  70. In search of a function for the Ras-like GTPase Rap1.
    FEBS Lett. 1997 Jun 23;410(1):59-62 PMID: 9247123
  71. 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):845-50 PMID: 9266971
  72. 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):22215-20 PMID: 9268367
  73. 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):1043-9 PMID: 9285558
  74. Maintenance of human T cell anergy: blocking of IL-2 gene transcription by activated Rap1.
    Science. 1997 Oct 3;278(5335):124-8 PMID: 9311917
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/17.23.6776
Email
[email protected]
Published
1998-12-01
Pages
6776-82
Language
English
Region
England
NLM ID
8208664
PMCID
PMC1171024
Subset
IM
External Links
PubMed source DOI: 10.1093/emboj/17.23.6776 PMC Full Text View journal details
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