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.

  • Review Article
  • Published:

Function of Rho family proteins in actin dynamics during phagocytosis and engulfment

Abstract

Phagocytosis is the uptake of large particles by cells by a mechanism that is based on local rearrangement of the actin microfilament cytoskeleton. In higher organisms, phagocytic cells are essential for host defence against invading pathogens, and phagocytosis contributes to inflammation and the immune response. In addition, engulfment, defined as the phagocytic clearance of cell corpses generated by programmed cell death or apoptosis, has an essential role in tissue homeostasis. Although morphologically distinct phagocytic events can be observed depending on the type of surface receptor engaged, work over the past two years has revealed the essential underlying role of Rho family proteins and their downstream effectors in controlling actin dynamics during phagocytosis.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: A model for FcγR-mediated phagocytosis.
Figure 2: A model for CR3-mediated phagocytosis.
Figure 3: The engulfment of apoptotic cells.

Similar content being viewed by others

References

  1. Rabinovitch, M. Professional and non-professional phagocytes: an introduction. Trends Cell Biol. 5, 85–87 (1995).

    Article  CAS  Google Scholar 

  2. Aderem, A. & Underhill, D. M. Mechanisms of phagocytosis in macrophages. Annu. Rev. Immunol. 17, 593–623 (1999).

    Article  CAS  Google Scholar 

  3. Stahl, P. D. & Ezekowitz, R. A. The mannose receptor is a pattern recognition receptor involved in host defense. Curr. Opin. Immunol. 10, 50–55 (1998).

    Article  CAS  Google Scholar 

  4. Greenberg, S. Signal transduction of phagocytosis. Trends. Biochem. Sci. 5, 93–97 (1995).

    CAS  Google Scholar 

  5. Kaplan, G. Differences in the mode of phagocytosis with Fc and C3 receptors in macrophages. Scand. J. Immunol. 6, 797–807 (1977).

    Article  CAS  Google Scholar 

  6. Allen, L. A. & Aderem, A. Molecular definition of distinct cytoskeletal structures involved in complement-and Fc receptor-mediated phagocytosis in macrophages. J. Exp. Med. 184, 627–637, (1996).

    Article  CAS  Google Scholar 

  7. Franc, N. C., White, K. & Ezekowitz, R. A. Phagocytosis and development: back to the future. Curr. Opin. Immunol. 11, 47–52, (1999).

    Article  CAS  Google Scholar 

  8. Reddien, P. W. & Horvitz, H. R. CED-2 /CrkII and CED-10 /Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nature Cell Biol. 2, 131–136, (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Mackay, D. J. & Hall, A. Rho GTPases. J. Biol. Chem. 273, 20685–20688, (1998).

    Article  CAS  Google Scholar 

  11. Bishop, A. L. & Hall, A. Rho GTPases and their effector proteins. Biochem. J. 348, 241–255, (2000).

    Article  CAS  Google Scholar 

  12. Daëron, M. Fc receptor biology. Annu. Rev. Immunol. 15, 203–234, (1997).

    Article  Google Scholar 

  13. Crowley, M. T. et al. A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages. J. Exp. Med. 186, 1027–1039, (1997).

    Article  CAS  Google Scholar 

  14. Cox, D., Tseng, C. C., Bjekic, G. & Greenberg, S. A requirement for phosphatidylinositol 3-kinase in pseudopod extension. J. Biol. Chem. 274, 1240–1247, (1999).

    Article  CAS  Google Scholar 

  15. Araki, N., Johnson, M. T. & Swanson, J. A. A role for phosphoinositide 3-Kinase in the completion of macropinocytosis and phagocytosis by macrophages. J. Cell Biol. 135, 1249–1260, (1996).

    Article  CAS  Google Scholar 

  16. Allen, W. E., Jones, G. E., Pollard, J. W. & Ridley, A. J. Rho, Rac and Cdc42 regulate actin organization and cell adhesion in macrophages. J. Cell Sci. 110, 707–720, (1997).

    CAS  PubMed  Google Scholar 

  17. Allen, W. E., Zicha, D., Ridley, A. J. & Jones, G. E. A role for Cdc42 in macrophage chemotaxis. J. Cell Biol. 141, 1147–1157, (1998).

    Article  CAS  Google Scholar 

  18. 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 

  19. 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 

  20. Hackam, D. J., Rotstein, O. D., Schreiber, A., Zhang Wj, & Grinstein, S. Rho is required for the initiation of calcium signaling and phagocytosis by fcgamma receptors in macrophages. J. Exp. Med. 186, 955–966, (1997).

    Article  CAS  Google Scholar 

  21. May, R. C., Caron, E., Hall, A. & Machesky, L. M. Involvement of the Arp2/3 complex in phagocytosis mediated by FcγR or CR3. Nature Cell Biol. xx, xxx–xxx (2000). [**AU: volume and page numbers?**]

    Google Scholar 

  22. Cox, D., Chang, P., Zhang, Q., Reddy, P. G., Bokoch, G. M. & Greenberg, S. Requirements for both rac1 and cdc42 in membrane ruffling and phagocytosis in leukocytes. J. Exp. Med. 186, 1487–1494, (1997).

    Article  CAS  Google Scholar 

  23. Carlier, M. F. Control of actin dynamics. Curr. Opin. Cell Biol. 10, 45–51, (1998).

    Article  CAS  Google Scholar 

  24. Bustelo, X. R. Regulatory and signaling properties of the Vav family. Mol. Cell Biol. 20, 1461–1477, (2000).

    Article  CAS  Google Scholar 

  25. Crespo, P., Schuebel, K. E., Ostrom, A. A., Gutkind, J. S. & Bustelo, X. R. Phosphotyrosine-dependent activation of RAc1 GDP/GTP exchange by the vav proto-oncogene product. Nature 285, 169–172, (1997).

    Article  Google Scholar 

  26. Han, J. et al. Role of substrates and products of PI 3-kinase in regulating activation of rac-related guanosine triphosphatases by Vav. Science 279, 558–560, (1998).

    Article  CAS  Google Scholar 

  27. Machesky, L. M. & Insall, R. H. Scar1 and the related wiskott-aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex. Curr. Biol. 8, 1347–1356, (1998).

    Article  CAS  Google Scholar 

  28. Machesky, L. M. & Gould, K. L. The Arp2/3 complex: a multifunctional actin organizer. Curr. Opin. Cell Biol. 11, 117–121, (1999).

    Article  CAS  Google Scholar 

  29. Borisy, G. G. & Svitkina, T. M. Actin machinery: pushing the envelope. Curr. Opin. Cell Biol. 12, 104–112, (2000).

    Article  CAS  Google Scholar 

  30. Zhang, J. et al. Antigen receptor-induced activation and cytoskeletal rearrangement are impaired in wiskott-aldrich syndrome protein-deficient lymphocytes. J. Exp. Med. 190, 1329–1342, (1999).

    Article  CAS  Google Scholar 

  31. Evans, E., Leung, A. & Zhelev, D. Synchrony of cell spreading and contraction force as phagocytes engulf large pathogens. J. Cell Biol. 122, 1295–1300, (1993).

    Article  CAS  Google Scholar 

  32. Swanson, J. A., Johnson, M. T., Beningo, K., Post, P., Mooseker, M. & Araki, N. A contractile activity that closes phagosomes in macrophages. J. Cell Sci. 112, 307–316, (1999).

    CAS  Google Scholar 

  33. Dharmawardhane, S., Brownson, D., Lennartz, M. & Bokoch, G. M. Localization of p21-activated kinase one, (PAK1) to pseudopodia, membrane ruffles, and phagocytic cups in activated human neutrophils. J. Leukoc. Biol. 66, 521–527, (1999).

    Article  CAS  Google Scholar 

  34. Sanders, L. C., Matsumura, F., Bokoch, G. M. & de Lanerolle, P. Inhibition of myosin light chain kinase by p21-activated kinase. Science 283, 2083–2085, (1999).

    Article  CAS  Google Scholar 

  35. van Leeuwen, F. N., van Delft, S., Kain, H. E., van der Kammen, R. A. & Collard, J. G. Rac regulates phosphorylation of the myosin-II heavy chain, actinomyosin disassembly and cell spreading. Nat.ure Cell Biol. 1, 242–248, (1999).

    Article  CAS  Google Scholar 

  36. Greenberg, S., el Khoury, J., di Virgilio, F., Kaplan, E. M. & Silverstein, S. C. Ca(2-independent F-actin assembly and disassembly during Fc receptor-mediated phagocytosis in mouse macrophages. J. Cell Biol. 113, 757–767, (1991).

    Article  CAS  Google Scholar 

  37. Hunter, S., Indik, Z. K., Kim, M. K., Cauley, M. D., Park, J. G. & Schreiber, A. D. Inhibition of Fcgamma Receptor-Mediated Phagocytosis by a Nonphagocytic Fcgamma Receptor. Blood 91, 1762–1768, (1998).

    CAS  PubMed  Google Scholar 

  38. Wu, Y., Spencer, S. D. & Lasky, L. A. Tyrosine phosphorylation regulates the SH3-mediated binding of the Wiskott-Aldrich syndrome protein to PSTPIP, a cytoskeletal-associated protein. J. Biol. Chem. 273, 5765–5770, (1998).

    Article  CAS  Google Scholar 

  39. Spencer, S. et al. PSTPIP: a tyrosine phosphorylated cleavage furrow-associated protein that is a substrate for a PEST tyrosine phosphatase. J. Cell Biol. 138, 845–860, (1997).

    Article  CAS  Google Scholar 

  40. Maresco, D. L., Osborne, J. M., Cooney, D., Coggeshall, K. M. & Anderson, C. L. The SH2-containing 5′-inositol phosphatase, (SHIP) is tyrosine phosphorylated after Fc gamma receptor clustering in monocytes. J. Immunol. 162, 6458–6465, (1999).

    CAS  PubMed  Google Scholar 

  41. Carroll, M. C. The role of complement and complement receptors in induction and regulation of immunity. Annu. Rev. Immunol. 16, 545–568, (1998).

    Article  CAS  Google Scholar 

  42. Berton, G. & Lowell, C. A. Integrin signalling in neutrophils and macrophages. Cell Signal. 11, 621–635, (1999).

    Article  CAS  Google Scholar 

  43. Kwiatkowska, K. & Sobota, A. Signaling pathways in phagocytosis. BioEssays 21, 422–431, (1999).

    Article  CAS  Google Scholar 

  44. Schoenwaelder, S. M. & Burridge, K. Bidirectional signaling between the cytoskeleton and integrins. Curr. Opin. Cell Biol. 11, 274–286, (1999).

    Article  CAS  Google Scholar 

  45. Ren, Y. & Savill, J. Apoptosis: the importance of being eaten. Cell Death. Differ. 5, 563–568, (1998).

    Article  CAS  Google Scholar 

  46. Hughes, J., Liu, Y., Van Damme, J. & Savill, J. Human glomerular mesangial cell phagocytosis of apoptotic neutrophils: mediation by a novel CD36-independent vitronectin receptor/thrombospondin recognition mechanism that is uncoupled from chemokine secretion. J. Immunol. 158, 4389–4397, (1997).

    CAS  PubMed  Google Scholar 

  47. Finnemann, S. C. & Rodriguez-Boulan, E. Macrophage and retinal pigment epithelium phagocytosis: apoptotic cells and photoreceptors compete for alphavbeta3 and alphavbeta5 integrins, and protein kinase C regulates alphavbeta5 binding and cytoskeletal linkage. J. Exp. Med. 190, 861–874, (1999).

    Article  CAS  Google Scholar 

  48. Fadok, V. A., Bratton, D. L., Frasch, S. C., Warner, M. L. & Henson, P. M. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death. Differ. 5, 551–562, (1998).

    Article  CAS  Google Scholar 

  49. Fadok, V. A., Bratton, D. L., Rose, D. M., Pearson, A., Ezekewitz, A. B. & Henson, P. M. A new receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90, (2000).

    Article  CAS  Google Scholar 

  50. Ellis, R. E., Yuan, J. Y. & Horvitz, H. R. Mechanisms and functions of cell death. Annu. Rev. Cell Biol. 7, 663–698, (1991).

    Article  CAS  Google Scholar 

  51. 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 

  52. 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 

  53. Kiyokawa, E., Hashimoto, Y., Kobayashi, S., Sugimura, H., Kurata, T. & Matsuda, M. Activation of Rac1 by a Crk SH3-binding protein, DOCK180. Genes. Dev. 12, 3331–3336, (1998).

    Article  CAS  Google Scholar 

  54. 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 

  55. Erickson, M. R., 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 

  56. Nolan, K. M., Barrett, K., Lu, Y., Hu, K. Q., Vincent, S. & Settleman, J. 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 

  57. Savill, J. Apoptosis. Phagocytic docking without shocking. Nature 392, 442–443, (1998).

    Article  CAS  Google Scholar 

  58. 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 

  59. 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 

  60. Luciani, M. F. & Chimini, G. The ATP binding cassette transporter ABC1, is required for the engulfment of corpses generated by apoptotic cell death. EMBO J. 15, 226–235, (1996).

    Article  CAS  Google Scholar 

  61. Hamon, Y. et al. ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine. Nature Cell Biol. 2, 399–406, (2000).

    Article  CAS  Google Scholar 

  62. Marguet, D., Luciani, M. F., Moynault, A., Williamson, P. & Chimini, G. Engulfment of apoptotic cells involves the redistribution of membrane phosphatidylserine on phagocyte and prey. Nature Cell Biol. 1, 454–456, (1999).

    Article  CAS  Google Scholar 

  63. Liu, Q. A. & Hengartner, M. O. Human CED-6 encodes a functional homologue of the Caenorhabditis elegans engulfment protein CED-6. Curr. Biol. 9, 1347–1350, (1999).

    Article  CAS  Google Scholar 

  64. Smits, E., Van Criekinge, W., Plaetinck, G. & Bogaert, T. The human homologue of Caenorhabditis elegans CED-6 specifically promotes phagocytosis of apoptotic cells. Curr. Biol. 9, 1351–1354, (1999).

    Article  CAS  Google Scholar 

  65. Su, H. P. et al. Identification and characterization of a dimerization domain in CED-6, an adapter protein involved in engulfment of apoptotic cells. J. Biol. Chem. 275, 9542–9549, (2000).

    Article  CAS  Google Scholar 

  66. Bajno, L., Peng, X. R., Schreiber, A. D., Moore, H. P., Trimble, W. S. & Grinstein, S. Focal exocytosis of VAMP3-containing vesicles at sites of phagosome formation. J. Cell Biol. 149, 697–706, (2000).

    Article  CAS  Google Scholar 

  67. Corvera, S. & Czech, M. P. Direct targets of phosphoinositide 3-kinase products in membrane traffic and signal transduction. Trends Cell Biol. 8, 442–446, (1998).

    Article  CAS  Google Scholar 

  68. Bretscher, M. S. & Aguado-Velasco, C. EGF induces recycling membrane to form ruffles. Curr. Biol. 8, 721–724, (1998).

    Article  CAS  Google Scholar 

  69. Bretscher, M. S. & Aguado-Velasco, C. Membrane traffic during cell locomotion. Curr. Opin. Cell Biol. 10, 537–541, (1998).

    Article  CAS  Google Scholar 

  70. Kroschewski, R., Hall, A. & Mellman, I. Cdc42 controls secretory and endocytic transport to the basolateral plasma membrane of MDCK cell. Nature Cell Biol. 1, 8–13, (1999).

    Article  CAS  Google Scholar 

  71. Chavrier, P. & Goud, B. The role of ARF and rab GTPases in membrane transport. Curr. Opin. Cell Biol. 11, 466–475, (1999).

    Article  CAS  Google Scholar 

  72. Zhang, Q., Cox, D., Tseng, C. C., Donaldson, J. G. & Greenberg, S. A requirement for ARF6 in Fcgamma receptor-mediated phagocytosis in macrophages. J. Biol. Chem. 273, 19977–19981, (1998).

    Article  CAS  Google Scholar 

  73. Cox, D., Lee, D. J., Dale, B. M., Calafat, J. & Greenberg, S. A Rab11-containing rapidly recycling compartment in macrophages that promotes phagocytosis. Proc. Natl Acad. Sci. USA 97, 680–685, (2000).

    Article  CAS  Google Scholar 

  74. Gershov, D. & Elkon, K. B. Complement-dependent clearance of apoptotic cells by human macrophages. J. Exp. Med. b, 2313–2320, (1998).

    Google Scholar 

  75. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nature Genet. 19, 56–59, (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are most grateful to M. Beckerle, F. Castellano, L. Machesky, D. Marguet, and R.C. May for their comments and advice on this manuscript. C. Beziers la Fosse is acknowledged for skillful assistance in the preparation of figures.

Author information

Authors and Affiliations

Authors

Additional information

Note added in proof: Very recent data have established that the CED-2/CED-5/CED-10 signalling pathway, which controls engulfment in C. elegans, is evolutionarily conserved and functionally analogous in mammalian cells to the integrin-triggered assembly of the CrkII/Dock180/Rac1 molecular complex (Albert, M. I., Kim, J-I. and Birge, R. The aub5 integrin recruits the CrkII/Dock180/Rac1 molecular complex for phagocytosis of apoptotic cells. Nature Cell Biol., in the press).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chimini, G., Chavrier, P. Function of Rho family proteins in actin dynamics during phagocytosis and engulfment. Nat Cell Biol 2, E191–E196 (2000). https://doi.org/10.1038/35036454

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35036454

This article is cited by

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