The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

let-60  -  Protein LET-60

Caenorhabditis elegans

Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

High impact information on let-60

  • Here we show that the let-7 family negatively regulates let-60/RAS [1].
  • Our genetic analysis showed ksr-1 positively mediates Ras signaling and functions downstream of or in parallel to let-60 [2].
  • Genetic epistasis analysis suggests that ksr-1 acts downstream of or in parallel to let-60 ras [3].
  • Extrachromosomal arrays of let-60 ras DNA cause cell-type misspecification (extra vulval fates) phenotypically opposite to that caused by let-60 ras loss-of-function mutations (no vulval fates), and suppress the vulvaless phenotype of mutations in two other genes necessary for vulval induction [4].
  • We have cloned the let-60 gene, and shown that it encodes a gene product identical in 84% of its first 164 amino acids to ras gene products from other vertebrate and invertebrate species [4].

Biological context of let-60

  • Genetic epistasis experiments indicate that lin-25 is required in the inductive signaling pathway downstream of let-60 Ras and the Raf/MAP kinase cascade [5].
  • Vulval development in the nematode Caenorhabiditis elegans can be divided into a fate specification phase controlled in part by let-60 Ras, and a fate execution phase involving stereotypical patterns of cell division and migration controlled in part by lin-17 Frizzled [6].
  • The let-60 ras gene of Caenorhabditis elegans is one of the key players in a signal transduction pathway that controls the choice between vulval and epidermal differentiation in response to extracellular signals [7].
  • Gain-of-function let-60 ras alleles rescued the defects associated with ptp-2(op194), suggesting that LET-60 Ras acts downstream of, or in parallel to, PTP-2 during oogenesis [8].
  • The penetrance of the multivulva phenotype caused by loss-of-function mutations in lin-15, and gain-of-function mutations in let-23 or let-60 ras, was reduced by ptp-2(op194) [8].

Anatomical context of let-60

  • The let-60 gene, an essential ras gene of the nematode Caenorhabditis elegans, acts as a switch in the inductive signalling pathway that initiates vulva formation [9].
  • A mosaic analysis demonstrated that let-60 ras is required within the sex myoblasts to control proper positioning [10].
  • Finally, we have also investigated genetic interactions between let-60 ras and other genes important for sex myoblast migration, including egl-15, which encodes a fibroblast growth factor receptor tyrosine kinase (D. L. DeVore, H. R. Horvitz and M. J. Stern (1995) Cell 83, 611-623) [10].
  • In Caenorhabditis elegans, let-60 Ras controls many cellular processes, such as differentiation of vulval epithelial cells, function of chemosensory neurons, and meiotic progression in the germ line [11].

Associations of let-60 with chemical compounds

  • Many genes required for vulval induction have been identified, including the let-23 receptor tyrosine kinase gene and the let-60 ras gene [12].
  • We show here that two farnesyltransferase inhibitors, manumycin and gliotoxin, suppress the Multivulva phenotype resulting from an activated let-60 ras mutation, but not the Multivulva phenotype resulting from mutations in the lin-1 gene or the lin-15 gene, which act downstream and upstream of let-60 ras, respectively, in the signaling pathway [13].

Regulatory relationships of let-60

  • A loss-of-function mutation in gap-1 suppresses the vulvaless phenotype of mutations in the let-60 ras signaling pathway, but a gap-1 single mutant does not exhibit excess vulval induction [14].
  • Consistent with its negative function, overexpressing sur-5 from an extragenic array partially suppresses the Multivulva phenotype of an activated let-60 ras mutation and causes synergistic phenotypes with a lin-45 raf mutation [15].
  • Mutants lacking lin-1 activity display a phenotype similar to that caused by mutations that constitutively activate let-60 Ras consistent with a model in which lin-1 is a repressor of the 1 degree fate whose activity is inhibited by phosphorylation by MPK-1 MAP kinase [16].
  • To identify components acting downstream of let-60 ras in the vulval signaling pathway, we have identified a reduction-of-function mutation in the sur-1 gene that completely suppresses the multivulva phenotype of a hyperactive let-60 ras mutation [7].
  • New genes that interact with lin-35 Rb to negatively regulate the let-60 ras pathway in Caenorhabditis elegans [17].

Other interactions of let-60

  • Microinjection of a gain-of-function mek-2 mutation resulted in Muv and other mutant phenotypes, whereas microinjection of a dominant-negative mutation not only suppressed the Muv phenotype of an activated let-60 ras mutation but also caused an egg-laying defective phenotype in otherwise wild type animals [18].
  • Genes necessary for this induction include the lin-3 growth factor, the let-23 receptor tyrosine kinase, and let-60 ras. lin-15 is a negative regulator of this inductive pathway [19].
  • We discuss the similarities and differences between the cellular defects seen in Rac mutants and let-60 Ras or lin-17 Frizzled mutants [6].
  • We identified cgr-1 by screening for suppressors of the ectopic vulval cell fates caused by a gain-of-function mutation of the let-60 ras gene [20].
  • C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation [21].

Analytical, diagnostic and therapeutic context of let-60


  1. RAS is regulated by the let-7 microRNA family. Johnson, S.M., Grosshans, H., Shingara, J., Byrom, M., Jarvis, R., Cheng, A., Labourier, E., Reinert, K.L., Brown, D., Slack, F.J. Cell (2005) [Pubmed]
  2. The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Kornfeld, K., Hom, D.B., Horvitz, H.R. Cell (1995) [Pubmed]
  3. The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. Sundaram, M., Han, M. Cell (1995) [Pubmed]
  4. let-60, a gene that specifies cell fates during C. elegans vulval induction, encodes a ras protein. Han, M., Sternberg, P.W. Cell (1990) [Pubmed]
  5. lin-25, a gene required for vulval induction in Caenorhabditis elegans. Tuck, S., Greenwald, I. Genes Dev. (1995) [Pubmed]
  6. ced-10 Rac and mig-2 function redundantly and act with unc-73 trio to control the orientation of vulval cell divisions and migrations in Caenorhabditis elegans. Kishore, R.S., Sundaram, M.V. Dev. Biol. (2002) [Pubmed]
  7. Suppression of activated Let-60 ras protein defines a role of Caenorhabditis elegans Sur-1 MAP kinase in vulval differentiation. Wu, Y., Han, M. Genes Dev. (1994) [Pubmed]
  8. The Caenorhabditis elegans SH2 domain-containing protein tyrosine phosphatase PTP-2 participates in signal transduction during oogenesis and vulval development. Gutch, M.J., Flint, A.J., Keller, J., Tonks, N.K., Hengartner, M.O. Genes Dev. (1998) [Pubmed]
  9. Caenorhabditis elegans ras gene let-60 acts as a switch in the pathway of vulval induction. Beitel, G.J., Clark, S.G., Horvitz, H.R. Nature (1990) [Pubmed]
  10. A Ras-mediated signal transduction pathway is involved in the control of sex myoblast migration in Caenorhabditis elegans. Sundaram, M., Yochem, J., Han, M. Development (1996) [Pubmed]
  11. Downstream targets of let-60 Ras in Caenorhabditis elegans. Romagnolo, B., Jiang, M., Kiraly, M., Breton, C., Begley, R., Wang, J., Lund, J., Kim, S.K. Dev. Biol. (2002) [Pubmed]
  12. C. elegans cell-signalling gene sem-5 encodes a protein with SH2 and SH3 domains. Clark, S.G., Stern, M.J., Horvitz, H.R. Nature (1992) [Pubmed]
  13. Ras farnesyltransferase inhibitors suppress the phenotype resulting from an activated ras mutation in Caenorhabditis elegans. Hara, M., Han, M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  14. Inhibition of Caenorhabditis elegans vulval induction by gap-1 and by let-23 receptor tyrosine kinase. Hajnal, A., Whitfield, C.W., Kim, S.K. Genes Dev. (1997) [Pubmed]
  15. Caenorhabditis elegans SUR-5, a novel but conserved protein, negatively regulates LET-60 Ras activity during vulval induction. Gu, T., Orita, S., Han, M. Mol. Cell. Biol. (1998) [Pubmed]
  16. lin-1 has both positive and negative functions in specifying multiple cell fates induced by Ras/MAP kinase signaling in C. elegans. Tiensuu, T., Larsen, M.K., Vernersson, E., Tuck, S. Dev. Biol. (2005) [Pubmed]
  17. New genes that interact with lin-35 Rb to negatively regulate the let-60 ras pathway in Caenorhabditis elegans. Thomas, J.H., Ceol, C.J., Schwartz, H.T., Horvitz, H.R. Genetics (2003) [Pubmed]
  18. MEK-2, a Caenorhabditis elegans MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events. Wu, Y., Han, M., Guan, K.L. Genes Dev. (1995) [Pubmed]
  19. The lin-15 locus encodes two negative regulators of Caenorhabditis elegans vulval development. Huang, L.S., Tzou, P., Sternberg, P.W. Mol. Biol. Cell (1994) [Pubmed]
  20. The CRAL/TRIO and GOLD domain protein CGR-1 promotes induction of vulval cell fates in Caenorhabditis elegans and interacts genetically with the Ras signaling pathway. Goldstein, J.L., Glossip, D., Nayak, S., Kornfeld, K. Genetics (2006) [Pubmed]
  21. C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation. Han, M., Golden, A., Han, Y., Sternberg, P.W. Nature (1993) [Pubmed]
  22. Ring formation drives invagination of the vulva in Caenorhabditis elegans: Ras, cell fusion, and cell migration determine structural fates. Shemer, G., Kishore, R., Podbilewicz, B. Dev. Biol. (2000) [Pubmed]
WikiGenes - Universities