RAS-Mediated Signal Transduction in C. elegans

  • Min Han
  • Meera Sundaram


The RAS-mediated signal transduction pathway, which is highly conserved among eukaryotes, plays key roles in multiple cellular and developmental processes including cell proliferation, differentiation and migration. In recent years, a combination of biochemical and genetic studies has allow scientists to identify many key players involved in RAS-mediated signal transduction and has begun to elucidate the mechanisms of activation and regulation of this pathway (see other chapters in this book). From receptor tyrosine kinases (RTKs) to RAS to MAP kinases, the main signal transduction pathway has been well established. The connections between this pathway and several other major signal transduction pathways have also begun to be revealed.


Caenorhabditis Elegans Inductive Signal Anchor Cell Vulval Development Larval Lethality 
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  1. 1.
    Sulston J, Horvitz HR. Postembryonic cell lineages of the nematode Caenorhabditis elegans. Devel Biol 1977; 56:110–56.CrossRefGoogle Scholar
  2. 2.
    Sundaram M, Han M. Control and integration of cell signaling pathways during C. elegans vulval development. BioEssay 1996; 18:473–480.CrossRefGoogle Scholar
  3. 3.
    Sternberg PW. Intercellular signaling and signal transduction in C. elegans. Annu Rev Genet 1993; 27:497–521.PubMedCrossRefGoogle Scholar
  4. 4.
    Katz WS, Hill RJ, Clandinin TR et al. Different levels of the C. elegans growth factor LIN-3 promote distinct vulval precursor fates. Cell 1995; 82:297–307.PubMedCrossRefGoogle Scholar
  5. 5.
    Ferguson E, Horvitz HR. The multivulva phenotype of certain C. elegans mutants results from defects in two functionally-redundant pathways. Genetics 1989; 123:109–21.PubMedGoogle Scholar
  6. 6.
    Herman RK, Hedgecock EM. Limitation of the size of the vulval primordium of Caenorhabditis elegans by lin-15 expression in surrounding hypodermis. Nature 1990; 348:169–71.PubMedCrossRefGoogle Scholar
  7. 7.
    Greenwald I, Rubin GM. Making a Difference: the role of cell-cell interactions in establishing separate identities for equivalent cells. Cell 1992; 68:271–81.PubMedCrossRefGoogle Scholar
  8. 8.
    Horvitz HR, Sternberg PW. Multiple intercellular signaling systems control the development of the C. elegans vulva. Nature 1991; 351:535–41.PubMedCrossRefGoogle Scholar
  9. 9.
    Sternberg PW. Intercellular signaling and signal transduction in C. elegans. Ann Rev Genet 1993; 27:497–521.PubMedCrossRefGoogle Scholar
  10. 10.
    Horvitz HR, Sulston JE. Isolation and genetic characterization of cell-lineage mutants of the nematode Caenorhabditis elegans. Genetics 1980; 96:435–54.PubMedGoogle Scholar
  11. 11.
    Greenwald IS, Sternberg PW, Horvitz HR. The lin-12 locus specifies cell fates in Caenorhabditis elegans. Cell 1983; 34:435–44.PubMedCrossRefGoogle Scholar
  12. 12.
    Ferguson E, Horvitz HR. Identification and characterization of 22 genes that affect the vulval cell lineages of Caenorhabditis elegans. Genetics 1985; 110:17–72.PubMedGoogle Scholar
  13. 13.
    Ferguson EL, Sternberg PW, Horvitz HR. A genetic pathway for the specification of the vulval cell lineages of Caenorhabditis elegans. Nature 1987; 326:259–67.PubMedCrossRefGoogle Scholar
  14. 14.
    Han M, Aroian R, Sternberg PW. The let-60 locus controls the switch between vulval and non-vulval cell types in C. elegans. Genetics 1990; 126:899–913.PubMedGoogle Scholar
  15. 15.
    Beitel G, Clark S, Horvitz HR. The Caenorhabditis elegans ras gene let-60 acts as a switch in the pathway of vulval induction. Nature 1990; 348:503–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Aroian RV, Sternberg PW. Multiple functions of let-23, a Caenorhabditis. elegans receptor tyrosine kinase gene required for vulval induction. Genetics 1991; 128:251–67.PubMedGoogle Scholar
  17. 17.
    Clark SG, Stern MJ, Horvitz HR. C. elegans cell-signaling gene sem-5 encodes a protein with SH2 and SH3 domain. Nature 1992; 356:340–4.PubMedCrossRefGoogle Scholar
  18. 18.
    Clark SG, Stern MJ, Horvitz HR. Genes involved in two Caenorhabditis elegans cell-signaling pathways. Cold Spring Harbor Symposia on Quantitative Biology 1992; LVII: 363–73.Google Scholar
  19. 19.
    Han M, Golden A, Han Y et al. C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation. Nature 1993; 363:133–40.PubMedCrossRefGoogle Scholar
  20. 20.
    Lackner MR, Kornfeld K, Miller LM et al. A MAP kinase homolog, mpk-1, is involved in ras-mediated induction of vulval cell fates in C. elegans. Genes Dev 1994; 8:160–73.PubMedCrossRefGoogle Scholar
  21. 21.
    Wu Y, Han M. Suppression of activated Let-60 RAS protein defines a role of Caenorhabditis elegans sur-1 MAP kinase in vulval differentiation. Genes Dev 1994; 8:147–59.PubMedCrossRefGoogle Scholar
  22. 22.
    Wu Y, Han M, Guan KL. MEK-2, a Caenorhabditis elegans MAP kinase kinase, function in RAS-mediated vulval induction and other developmental events. Genes & Development 1995; 9:742–55.CrossRefGoogle Scholar
  23. 23.
    Kornfeld K, Guan KL, Horvitz HR. The C. elegans gene mek-2 is required for vulval induction and encodes a protein similar to the protein kinase MEK. Gen & Devel 1995; 9:757–67.Google Scholar
  24. 24.
    Kornfeld K, Hom DB, Horvitz HR. The ksr-1 gene encodes a novel protein kinase involved in RAS-mediated signaling in Caenorhabditis elegans. Cell 1995b; 902–13.Google Scholar
  25. 25.
    Singh N, Han M. sur-2, a novel gene, functions late in the let-60 ras-mediated signaling pathway during Caenorhabditis elegans vulval induction. Gen & Devel 1995; 9:2251–65.CrossRefGoogle Scholar
  26. 26.
    Tuck S, Greenwald I. lin-25, a gene required for vulval induction in Caenorhabditis elegans. Genes & Dev 1995; 9:341–57.CrossRefGoogle Scholar
  27. 27.
    Sundaram M, Han M. The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in RAS-mediated signal transduction. Cell 1995; 83:889–901.PubMedCrossRefGoogle Scholar
  28. 28.
    Lee JG, Jongeward G, Sternberg PW. The C. elegans unc-101 gene, required for development and behavior, encodes a clathrin-associated protein. Genes Devel 1994; 8:60–73.PubMedCrossRefGoogle Scholar
  29. 29.
    Jongeward GD, Clandinin TR, Sternberg PW. sli-1, a negative regulator of let-23-mediated signaling in C. elegans. Genetics 1995; 139:1553–66.PubMedGoogle Scholar
  30. 30.
    Trent C, Tsung N, Horvitz HR. Egg-laying defective mutants of the nematode Caenorhabditis elegans. Genetics 1983; 104:619–47.PubMedGoogle Scholar
  31. 31.
    Wassarman DA, Thierrien M, Rubin GM. The RAS signaling pathway in Drosophila. Curr Opin Gen Dev 1995; 5:44–51.CrossRefGoogle Scholar
  32. 32.
    Rogalski TM, Moerman DG, Baillie DL. Essential genes and deficiencies in the unc-22 IV region of Caenorhabditis elegans. Genetics 1982; 102:725–36.PubMedGoogle Scholar
  33. 33.
    Clark DV, Rogalski TM, Donati LM et al. The unc-22(IV) region of Caenorhabditis elegans: genetic analysis of lethal mutations. Genetics 1988; 119:345–53.PubMedGoogle Scholar
  34. 34.
    Howe LR, Marshall CJ. Identification of amino acids in P21 ras involved in exchange factor interaction. Oncogene 1993; 8:2583–90.PubMedGoogle Scholar
  35. 35.
    Han M, Sternberg PW. let-60, a gene that specifies cell fates during C. elegans vulval induction, encodes a ras protein. Cell 1990; 63:921–31.PubMedCrossRefGoogle Scholar
  36. 36.
    Han M, Sternberg PW. Analysis of dominant-negative mutations of the Caenorhabditis elegans let-60 ras gene. Genes Dev 1991; 5:2188–98.PubMedCrossRefGoogle Scholar
  37. 37.
    Sigal IS, Gibbs JB, D’Alonzo JS et al. Mutant ras-encoded proteins with altered nucleotide binding exert dominant biological effects. Proc Natl Acad Sci USA 1986; 83:952–6.PubMedCrossRefGoogle Scholar
  38. 38.
    Hill RJ, Sternberg PW. The gene lin-3 encodes an inductive signal for vulval development in C. elegans. Nature 1992; 358:470–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Katz WS, Lesa GM, Yannoukakos D et al. A point mutation in the extracellular domain activates LET-23, the C. elegans EG F receptor homolog. Mole Cell Biol 1996; (in press).Google Scholar
  40. 40.
    Herman RK. Crossover suppressors and balanced recessive lethals in Caenorhabditis elegans. Genetics 1978; 88:49–65.PubMedGoogle Scholar
  41. 41.
    Sigurdson DC, Spanier GJ, Herman RK. Caenorhabditis elegans deficiency mapping. Genetics 1984; 108:331–45.PubMedGoogle Scholar
  42. 42.
    Aroian RV, Koga M, Mendel JE et al. The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily. Nature 1990; 348:693–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Aroian RV, Lesa GM, Sternberg PW. Mutations in the Caenorhabditis elegans let-23 EGFR-like gene define elements important for cell-type specificity and function. EMBO J 1994; 13:360–6.PubMedGoogle Scholar
  44. 44.
    Simske JS, Kim SK. Sequential signaling during C. elegans vulval induction. Nature 1995; 375:142–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Koga M, Ohshima Y. Mosaic analysis of the let-23 gene function in vulval induction of Caenorhabditis elegans. Devel 1995; 121:2655–66.Google Scholar
  46. 46.
    Sternberg PW, Horvitz HR. The combined action of two intercellular signaling pathways specifies three cell fates during vulval induction in C. elegans. Cell 1989; 58:679–93.PubMedCrossRefGoogle Scholar
  47. 47.
    Johnsen RC, Baillie DL. Genetic analysis of a major segment [LGV(left)] of the genome of Caenorhabditis elegans. Genetics 1991; 129:735.PubMedGoogle Scholar
  48. 48.
    Lowenstein EJ, Daly RJ, Batzer AG et al. The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 1992; 70:431–42.PubMedCrossRefGoogle Scholar
  49. 49.
    Stern MJ, Marengere LEM, Daly RJ et al. The human GRB2 and Drosophila Drk genes can functionally replace the Caenorhabditis elegans cell signaling gene sem-5. Mol Biol Cell 1993; 4:1175–88.PubMedGoogle Scholar
  50. 50.
    McCormick F. How receptors turn RAS on. 1993; 363:15–6.Google Scholar
  51. 51.
    Huang LS, Tzou P, Sternberg PW. The lin-15 locus encodes two negative regulators of Caenorhabditis elegans vulval development. Molecular Biology of the Cell 1994; 5:395–411.PubMedGoogle Scholar
  52. 52.
    Clark SG, Lu X, Horvitz HR. The Caenorhabditis elegans locus lin-15, a negative regulator of a tyrosine kinase signaling pathway, encodes two different proteins. Genetics 1994; 137:987–97.PubMedGoogle Scholar
  53. 53.
    Sulston JE, Horvitz HR. Abnormal cell lineages in mutants of the nematode Caenorhabditis elegans. Dev Biol 1981; 82:41–55.PubMedCrossRefGoogle Scholar
  54. 54.
    Hedgecock EM, Herman RK. The ncl-1 gene and genetic mosaics of Caenorhabditis elegans. Genet 1995; 141:989–1006.Google Scholar
  55. 55.
    Sternberg PW, Yoon CH, Lee J et al. Molecular genetics of proto-oncogenes and candidate tumor suppressors in Caenorhabditis elegans. Cold Spring Harbor Symp Quant Biol 1994; LIX: 155–63.Google Scholar
  56. 56.
    Thomas JH. Genetic analysis of defecation in Caenorhabditis elegans. Genetics Society of America 1990; 124:855–72.Google Scholar
  57. 57.
    Schmid SL. The mechanism of receptor-mediated endocytosis. BioEssays 1992; 14:589–96.PubMedCrossRefGoogle Scholar
  58. 58.
    Peyrard M, Fransson I, Xie YG et al. Characterization of a new member of the human B-adaptin gene family from chromosome 22q12, a candidate meningioma gene. Hum Mol Genet 1994; 3:1393–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Blake TJ, Shapiro M, Morse HC et al. The sequences of the human and mouse c-cbl proto-oncogenes show v-cbl was generated by a large truncation encompassing a proline-rich doman and a leucine zipper-like motif. Oncogene 1991; 6:653-.PubMedGoogle Scholar
  60. 60.
    Yoon CH, Lee J, Jongeward GD et al. Similarity of sli-1, a regulator of vulval development in C. elegans, to the mammalian proto-oncogene c-cbl. Sci 1995; 269:Google Scholar
  61. 61.
    Hoskins R, Hajnal AF, Harp SA et al. The C. elegans vulval induction gene lin-2 encodes a member of the MAGUK family of cell junction proteins. Devel 1996; (in press).Google Scholar
  62. 62.
    Kim SK. Tight junctions, membrane-associated guanylate kinases and cell signaling. Curr Opin Cell Biol 1995; 7:641–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Kim SK, Horvitz HR. The Caenorhabditis elegans gene lin-10 is broadly expressed while required specifically for the determination of vulval cell fates. Genes & Devel 1990; 4:357–71.CrossRefGoogle Scholar
  64. 64.
    Chuch DL, Guan KL, Lambie EJ. mek-2, mpk-l/sur-1 and let-60 ras are required for meiotic cell cycle progression in C. elegans. Develop 1995; 121:2525–35.Google Scholar
  65. 65.
    McKim KS. (The University of British Columbia, Vancouver, British Columbia, Canada., 1990).Google Scholar
  66. 66.
    Therrien M, Chang HC, Solomon NM et al. KSR, a novel protein kinase required for RAS signal transduction. Cell 1995; 83:879–87.PubMedCrossRefGoogle Scholar
  67. 67.
    Beitel GJ, Tuck S, Greenwald IS et al. The C. elegans gene lin-1 encodes an ETS-domain protein and defines a branch of the vulval induction pathway. Genes Dev 1996; 9:3149–62.CrossRefGoogle Scholar
  68. 68.
    Miller LM, Gallegos ME, Morisseau BA et al. Lin-31, a Caenorhabditis elegans HNF-3/fork head transcription factor homolog, specifies three alternative cell fates in vulval development. Genes & Dev 1993; 7:933–47.CrossRefGoogle Scholar
  69. 69.
    Chamberlin HM, Sternberg PW. The lin-3/let-23 pathway mediates inductive signaling during male speicule development in Caenorhabditis elegans. Development 1994; 120:2713–21.PubMedGoogle Scholar
  70. 70.
    Sulston JE. Post-embryonic development in the ventral cord of Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci 1976; 275:287–98.PubMedCrossRefGoogle Scholar
  71. 71.
    Sulston JE, White JG. Regulation and cell autonomy during postembryonic development of Caenorhabditis elegans. Devel Biol 1980; 78:577–97.CrossRefGoogle Scholar
  72. 72.
    Sternberg PW, Horvitz HR. Pattern formation during vulval development in Caenorhabditis elegans. Cell 1986; 44:761–72.PubMedCrossRefGoogle Scholar
  73. 73.
    Kimble J. Lineage alterations after ablation of cells in the somatic gonad of Caenorhabditis elegans. Dev Biol 1981; 87:286–300.PubMedCrossRefGoogle Scholar
  74. 74.
    Sternberg PW. Lateral inhibition during vulval induction in Caenorhabditis elegans. Nature 1988; 335:551–4.PubMedCrossRefGoogle Scholar

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© R.G. Landes Company 1996

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  • Min Han
  • Meera Sundaram

There are no affiliations available

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