Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans

Nature Cell Biology volume 2, pages 131–136 (2000)Cite this article

Abstract

Engulfment of apoptotic cells in Caenorhabditis elegans is controlled by two partially redundant pathways. Mutations in genes in one of these pathways, defined by the genes ced-2, ced-5 and ced-10, result in defects both in the engulfment of dying cells and in the migrations of the two distal tip cells of the developing gonad. Here we find that ced-2 and ced-10 encode proteins similar to the human adaptor protein CrkII and the human GTPase Rac, respectively. Together with the previous observation that ced-5 encodes a protein similar to human DOCK180, our findings define a signalling pathway that controls phagocytosis and cell migration. We provide evidence that CED-2 and CED-10 function in engulfing rather than dying cells to control the phagocytosis of cell corpses, that CED-2 and CED-5 physically interact, and that ced-10 probably functions downstream of ced-2 and ced-5. We propose that CED-2/CrkII and CED-5/DOCK180 function to activate CED-10/Rac in a GTPase signalling pathway that controls the polarized extension of cell surfaces.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The distal tip cell (DTC) reverses its direction of migration in a ced-2 mutant.
Figure 2: ced-2 and ced-10 encode proteins similar to human CrkII and Rac, respectively.
Figure 3: CED-2 and CED-5 interact.
Figure 4: Model for the control of phagocytosis in programmed cell death by ced-2, ced-5 and ced-10.

References

  1. Fadok, V. A. & Henson, P. M. Apoptosis: getting rid of the bodies. Curr. Biol. 8, R693–R695 (1998).

    Article  CAS  Google Scholar 

  2. Metzstein, M. M., Stanfield, G. M. & Horvitz, H. R. Genetics of programmed cell death in C. elegans: Past, present and future. Trends Genet. 14, 410–416 (1998).

    Article  CAS  Google Scholar 

  3. Adams, J. M. & Cory, S. The Bcl-2 family: arbiters of cell survival. Science 281, 322–326 (1998).

    Article  Google Scholar 

  4. Hedgecock, E. M., Sulston, J. E. & Thomson, J. N. Mutations affecting programmed cell deaths in the nematode Caenorhabditis elegans. Science 220, 1277–1279 (1983).

    Article  CAS  Google Scholar 

  5. Ellis, R. E., Jacobson, D. M. & Horvitz, H. R. Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans. Genetics 129, 79–94 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Wu, Y. C. & Horvitz, H. R. C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180. Nature 392, 501–504 (1998).

    Article  CAS  Google Scholar 

  7. Liu, Q. A. & Hengartner, M. O. Candidate adaptor protein CED-6 promotes the engulfment of apoptotic cells in C. elegans. Cell 93, 961–972 (1998).

    Article  CAS  Google Scholar 

  8. Wu, Y. C. & Horvitz, H. R. The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell 93, 951–960 (1998).

    Article  CAS  Google Scholar 

  9. Hasegawa, H. et al. DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane. Mol. Cell Biol. 16, 1770–1776 (1996).

    Article  CAS  Google Scholar 

  10. Erickson, M., Galletta, B. J. & Abmayr, S. M. Drosophila myoblast city encodes a conserved protein that is essential for myoblast fusion, dorsal closure, and cytoskeletal organization. J. Cell Biol. 138, 589–603 (1997).

    Article  CAS  Google Scholar 

  11. Kimble, J. & Hirsh, D. The postembryonic cell lineages of the hermaphrodite and male gonads in Caenorhabditis elegans. Dev. Biol. 70, 396–417 (1979).

    Article  CAS  Google Scholar 

  12. The C. elegans Sequencing Consortium. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282, 2012–2018 (1998).

  13. Matsuda, M. et al. Two species of human CRK cDNA encode proteins with distinct biological activities. Mol. Cell Biol. 12, 3482–3489 (1992).

    Article  CAS  Google Scholar 

  14. Mayer, B. J., Hamaguchi, M. & Hanafusa, H. A novel viral oncogene with structural similarity to phospholipase C. Nature 332, 272–275 (1988).

    Article  CAS  Google Scholar 

  15. Kiyokawa, E., Hashimoto, Y., Kurata, T., Sugimura, H. & Matsuda, M. Evidence that DOCK180 up-regulates signals from the CrkII-p130(Cas) complex. J. Biol. Chem. 273, 24479–24484 (1998).

    Article  CAS  Google Scholar 

  16. Klemke, R. L. et al. CAS/Crk coupling serves as a “molecular switch” for induction of cell migration. J. Cell Biol. 140, 961–972 (1998).

    Article  CAS  Google Scholar 

  17. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    Article  CAS  Google Scholar 

  18. Imaizumi, T. et al. Mutant mice lacking crk-II caused by the gene trap insertional mutagenesis: crk-II is not essential for embryonic development. Biochem. Biophys. Res. Commun. 266, 569–574 (1999).

    Article  CAS  Google Scholar 

  19. ten Hoeve, J., Morris, C., Heisterkamp, N. & Groffen, J. Isolation and chromosomal localization of CRKL, a human crk-like gene. Oncogene 8, 2469–2474 (1993).

    CAS  PubMed  Google Scholar 

  20. Alfonso, A., Grundahl, K., Duerr, J. S., Han, H. P. & Rand, J. B. The Caenorhabditis elegans unc-17 gene: a putative vesicular acetylcholine transporter. Science 261, 617–619 (1993).

    Article  CAS  Google Scholar 

  21. Li, W., Herman, R. K. & Shaw, J. E. Analysis of the Caenorhabditis elegans axonal guidance and outgrowth gene unc-33. Genetics 132, 675–689 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen, W., Lim, H. H. & Lim, L. A new member of the ras superfamily, the rac1 homologue from Caenorhabditis elegans. J. Biol. Chem. 268, 320–324 (1993).

    CAS  PubMed  Google Scholar 

  23. Van Aelst, L. & D"Souza-Schorey, C. Rho GTPases and signaling networks. Genes Dev. 11, 2295–2322 (1997).

    Article  CAS  Google Scholar 

  24. Caron, E. & Hall, A. Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 282, 1717–1721 (1998).

    Article  CAS  Google Scholar 

  25. Massol, P., Montcourrier, P., Guillemot, J. C. & Chavrier, P. Fc receptor-mediated phagocytosis requires CDC42 and Rac1. EMBO J. 17, 6219–6229 (1998).

    Article  CAS  Google Scholar 

  26. Kiyokawa, E. et al. Activation of Rac1 by a Crk SH3-binding protein, DOCK180. Genes Dev. 12, 3331–3336 (1998).

    Article  CAS  Google Scholar 

  27. Nolan, K. M. et al. Myoblast city, the Drosophila homolog of DOCK180/CED-5, is required in a Rac signaling pathway utilized for multiple developmental processes. Genes Dev. 12, 3337–3342 (1998).

    Article  CAS  Google Scholar 

  28. Li, L. & Cohen, S. N. Tsg101: a novel tumor susceptibility gene isolated by controlled homozygous functional knockout of allelic loci in mammalian cells. Cell 85, 319–329 (1996).

    Article  CAS  Google Scholar 

  29. Spieth, J., Brooke, G., Kuersten, S., Lea, K. & Blumenthal, T. Operons in C. elegans: polycistronic mRNA precursors are processed by trans-splicing of SL2 to downstream coding regions. Cell 73, 521–532 (1993).

    Article  CAS  Google Scholar 

  30. Zhang, F. L. & Casey, P. J. Protein prenylation: molecular mechanisms and functional consequences. Annu. Rev. Biochem. 65, 241–269 (1996).

    Article  CAS  Google Scholar 

  31. Reiss, Y., Stradley, S. J., Gierasch, L. M., Brown, M. S. & Goldstein, J. L. Sequence requirement for peptide recognition by rat brain p21ras protein farnesyltransferase. Proc. Natl Acad. Sci. USA 88, 732–736 (1991).

    Article  CAS  Google Scholar 

  32. Bourne, H. R., Sanders, D. A. & McCormick, F. The GTPase superfamily: conserved structure and molecular mechanism. Nature 349, 117–127 (1991).

    Article  CAS  Google Scholar 

  33. Sugihara, K. et al. Rac1 is required for the formation of three germ layers during gastrulation. Oncogene 17, 3427–3433 (1998).

    Article  CAS  Google Scholar 

  34. Gumienny, T. L., Lambie, E., Hartwieg, E., Horvitz, H. R. & Hengartner, M. O. Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline. Development 126, 1011–1022 (1999).

    CAS  PubMed  Google Scholar 

  35. Lauffenburger, D. A. & Horwitz, A. F. Cell migration: a physically integrated molecular process. Cell 84, 359–369 (1996).

    Article  CAS  Google Scholar 

  36. Platt, N., da Silva, R. P. & Gordon, S. Recognizing death: the phagocytosis of apoptotic cells. Trends Cell Biol. 8, 365–372 (1998).

    Article  CAS  Google Scholar 

  37. Mello, C. C., Kramer, J. M., Stinchcomb, D. & Ambros, V. Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 10, 3959–3970 (1991).

    Article  CAS  Google Scholar 

  38. Bloom, L. & Horvitz, H. R. The Caenorhabditis elegans gene unc-76 and its human homologs define a new gene family involved in axonal outgrowth and fasciculation. Proc. Natl Acad. Sci. USA 94, 3414–3419 (1997).

    Article  CAS  Google Scholar 

  39. Krause, M. & Hirsh, D. A trans-spliced leader sequence on actin mRNA in C. elegans. Cell 49, 753–761 (1987).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Hersh and R. Ranganathan for comments concerning this manuscript, and Y. Kohara for providing cDNA clones. P.W.R. was supported by a National Science Foundation Fellowship and an NIH training grant. H.R.H. is an Investigator of the Howard Hughes Medical Institute.

Correspondence and requests for materials should be addressed to H.R.H. The nucleotide sequences of ced-2 and ced-10 have been deposited at GenBank under accession numbers AF226866 and AF226867, respectively.

Author information

Authors and Affiliations

  1. Department of Biology, Howard Hughes Medical Institute, 68-425, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 02139, Cambridge, Massachusetts, USA

    Peter W. Reddien & H. Robert Horvitz

Authors
  1. Peter W. Reddien
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H. Robert Horvitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H. Robert Horvitz.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Reddien, P., Horvitz, H. CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nat Cell Biol 2, 131–136 (2000). https://doi.org/10.1038/35004000

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35004000

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing