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.

  • Article
  • Published:

A kinase cascade leading to Rab11-FIP5 controls transcytosis of the polymeric immunoglobulin receptor

Nature Cell Biology volume 12, pages 1143–1153 (2010)Cite this article

Subjects

This article has been updated

Abstract

Polymeric immunoglobulin A (pIgA) transcytosis, mediated by the polymeric immunoglobulin receptor (pIgR), is a central component of mucosal immunity and a model for regulation of polarized epithelial membrane traffic. Binding of pIgA to pIgR stimulates transcytosis in a process requiring Yes, a Src family tyrosine kinase (SFK). We show that Yes directly phosphorylates EGF receptor (EGFR) on liver endosomes. Injection of pIgA into rats induced EGFR phosphorylation. Similarly, in MDCK cells, pIgA treatment significantly increased phosphorylation of EGFR on various sites, subsequently activating extracellular signal-regulated protein kinase (ERK). Furthermore, we find that the Rab11 effector Rab11-FIP5 is a substrate of ERK. Knocking down Yes or Rab11-FIP5, or inhibition of the Yes–EGFR–ERK cascade, decreased pIgA–pIgR transcytosis. Finally, we demonstrate that Rab11-FIP5 phosphorylation by ERK controls Rab11a endosome distribution and pIgA–pIgR transcytosis. Our results reveal a novel Yes–EGFR–ERK–FIP5 signalling network for regulation of pIgA–pIgR transcytosis.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Identification of EGFR as a Yes substrate in rat liver endosomes.
Figure 2: EGFR phosphorylation is induced in rat liver endosomes, and in pIgR-expressing MDCK cells, on pIgA stimulation.
Figure 3: Interaction and co-localization of EGFR, pIgR and Yes.
Figure 4: pIgA-stimulated pIgR transcytosis requires EGFR activity.
Figure 5: ERK phosphorylation induced by pIgA treatment is required for pIgA–pIgR transcytosis in MDCK cells expressing pIgR.
Figure 6: FIP5 phosphorylation is downstream of Yes–EGFR–ERK.
Figure 7: FIP5 Ser 188 phosphorylation regulates Rab11a localization and pIgA–pIgR transcytosis.
Figure 8: A kinase cascade regulating pIgR transcytosis.

Similar content being viewed by others

Change history

  • 12 November 2010

    In the version of this article initially published online, the amount of protein from cell lysate used in immunoprecipitation assays was incorrect. In addition the paper describing the FIP5 cDNA was not referenced. These errors have been corrected in both the HTML and PDF versions of the article.

References

  1. Mellman, I. & Nelson, W. J. Coordinated protein sorting, targeting and distribution in polarized cells. Nat. Rev. Mol. Cell Biol. 9, 833–845 (2008).

    Article  CAS  Google Scholar 

  2. Weisz, O. A. & Rodriguez-Boulan, E. Apical trafficking in epithelial cells: signals, clusters and motors. J. Cell Sci. 122, 4253–4566 (2009).

    Article  CAS  Google Scholar 

  3. Sorkin, A. & von Zastrow, M. Endocytosis and signalling: intertwining molecular networks. Nat. Rev. Mol. Cell Biol. 10, 609–622 (2009).

    Article  CAS  Google Scholar 

  4. Mostov, K. E., Su, T. & ter Beest, M. Polarized epithelial membrane traffic: conservation and plasticity. Nat. Cell Biol. 5, 287–293 (2003).

    Article  CAS  Google Scholar 

  5. Rojas, R. & Apodaca, G. Immunoglobulin transport across polarized epithelial cells. Nat. Rev. Mol. Cell Biol. 3, 944–956 (2002).

    Article  CAS  Google Scholar 

  6. Song, W., Bomsel, M., Casanova, J., Vaerman, J.-P. & Mostov, K. E. Stimulation of transcytosis of the polymeric immunoglobulin receptor by dimeric IgA. Proc. Natl Acad. Sci. USA 91, 163–166 (1994).

    Article  CAS  Google Scholar 

  7. Giffroy, D. et al. In vivo stimulation of polymeric Ig receptor-transcytosis by circulating polymeric IgA in rat liver. Int. Immunol. 10, 347–354 (1998).

    Article  CAS  Google Scholar 

  8. Bomsel, M. & Mostov, K. Role of heterotrimeric G proteins in membrane traffic. Mol. Biol. Cell 3, 1317–1328 (1992).

    Article  CAS  Google Scholar 

  9. Kaetzel, C. S. The polymeric immunoglobulin receptor: bridging innate and adaptive immune responses at mucosal surfaces. Immunol. Rev. 206, 83–99 (2005).

    Article  CAS  Google Scholar 

  10. Tuma, P. L. & Hubbard, A. L. Transcytosis: crossing cellular barriers. Physiol. Rev. 83, 871–932 (2003).

    Article  CAS  Google Scholar 

  11. Song, W., Apodaca, G. & Mostov, K. Transcytosis of the polymeric immunoglobulin receptor is regulated in multiple intracellular compartments. J. Biol. Chem. 269, 29474–29480 (1994).

    CAS  PubMed  Google Scholar 

  12. van IJzendoorn, S. C. D., Tuvim, M. J., Weimbs, T., Dickey, B. F. & Mostov, K. E. Direct interaction between Rab3b and the polymeric immunoglobulin receptor controls ligand-stimulated transcytosis in epithelial cells. Dev. Cell 2, 219–228 (2002).

    Article  CAS  Google Scholar 

  13. Casanova, J. E. et al. Association of Rab25 and Rab11a with the apical recycling system of polarized Madin-Darby canine kidney cells. Mol. Biol. Cell 10, 47–61 (1999).

    Article  CAS  Google Scholar 

  14. Prekeris, R., Klumperman, J. & Scheller, R. H. A Rab11/Rip11 protein complex regulates apical membrane trafficking via recycling endosomes. Mol. Cell 6, 1437–1448 (2000).

    Article  CAS  Google Scholar 

  15. Luton, F., Vergés, M., Vaerman, J.-P., Sudol, M. & Mostov, K. E. The src family protein tyrosine kinase p62yes controls polymeric IgA transcytosis in vivo. Mol. Cell 4, 627–632 (1999).

    Article  CAS  Google Scholar 

  16. Shah, K., Liu, Y., Deirmengian, C. & Shokat, K. M. Engineering unnatural nucleotide specificity for Rous sarcoma virus tyrosine kinase to uniquely label its direct substrates. Proc. Natl Acad. Sci. USA 94, 3565–3570 (1997).

    Article  CAS  Google Scholar 

  17. Liu, Y., Shah, K., Yang, F., Witucki, L. & Shokat, K. M. Engineering Src family protein kinases with unnatural nucleotide specificity. Chem. Biol. 5, 91–101 (1998).

    Article  CAS  Google Scholar 

  18. Vergés, M., Havel, R. J. & Mostov, K. E. A tubular endosomal fraction from rat liver: biochemical evidence of receptor sorting by default. Proc. Natl Acad. Sci. USA 18, 10146–10151 (1999).

    Article  Google Scholar 

  19. Bishop, A. C. et al. A chemical switch for inhibitor-sensitive alleles of any protein kinase. Nature 407, 395–401 (2000).

    Article  CAS  Google Scholar 

  20. Mullock, B. M., Jones, R. S. & Hinton, R. H. Movement of endocytic shuttle vesicles from the sinusoidal to the bile canalicular face of hepatocytes does not depend on occupation of receptor sites. FEBS Lett. 113, 201–205 (1980).

    Article  CAS  Google Scholar 

  21. Apodaca, G., Katz, L. A. & Mostov, K. E. Receptor-mediated transcytosis of IgA in MDCK cells via apical recycling endosomes. J. Cell Biol. 125, 67–86 (1994).

    Article  CAS  Google Scholar 

  22. Jorissen, R. N. et al. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp. Cell Res. 284, 31–53 (2003).

    Article  CAS  Google Scholar 

  23. Haugh, J. M. Localization of receptor-mediated signal transduction pathways: the inside story. Mol. Interv. 2, 292–307 (2002).

    Article  CAS  Google Scholar 

  24. Luton, F., Cardone, M. H., Zhang, M. & Mostov, K. E. Role of tyrosine phosphorylation in ligand-induced regulation of transcytosis of the polymeric Ig receptor. Mol. Biol. Cell 9, 1787–1802 (1998).

    Article  CAS  Google Scholar 

  25. Li, B. X., Satoh, A. K. & Ready, D. F. Myosin V, Rab11 and dRip11 direct apical secretion and cellular morphogenesis in developing Drosophila photoreceptors. J. Cell Biol. 177, 659–669 (2007).

    Article  CAS  Google Scholar 

  26. Lapierre, L. A. et al. Myosin Vb is associated with plasma membrane recycling systems. Mol. Biol. Cell 12, 1843–1857 (2001).

    Article  CAS  Google Scholar 

  27. Hansen, S. H., Olsson, A. & Casanova, J. E. Wortmannin, an inhibitor of phosphoinositide 3-kinase, inhibits transcytosis in polarized epithelial cells. J. Biol. Chem. 270, 28425–28432 (1995).

    Article  CAS  Google Scholar 

  28. Vergés, M. et al. The mammalian retromer regulates transcytosis of the polymeric immunoglobulin receptor. Nat. Cell Biol. 6, 763–769 (2004).

    Article  Google Scholar 

  29. Verges, M., Sebastian, I. & Mostov, K. E. Phosphoinositide 3-kinase regulates the role of retromer in transcytosis of the polymeric immunoglobulin receptor. Exp. Cell Res. 313, 707–718 (2007).

    Article  CAS  Google Scholar 

  30. Luton, F., Hexham, M. J., Zhang, M. & Mostov, K. E. Identification of a cytoplasmic signal for apical transcytosis. Traffic 10, 1128–1142 (2009).

    Article  CAS  Google Scholar 

  31. Wang, X., Kumar, R., Navarre, J., Casanova, J. E. & Goldenring, J. R. Regulation of vesicle trafficking in Madin-Darby canine kidney cells by Rab11a and Rab25. J. Biol. Chem. 275, 29138–29146 (2000).

    Article  CAS  Google Scholar 

  32. Pawson, T. Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems. Cell 116, 191–203 (2004).

    Article  CAS  Google Scholar 

  33. Thelemann, A. et al. Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells. Mol. Cell Proteomics 4, 356–376 (2005).

    Article  CAS  Google Scholar 

  34. Wu, S. L. et al. Dynamic profiling of the post-translational modifications and interaction partners of epidermal growth factor receptor signaling after stimulation by epidermal growth factor using extended range proteomic analysis (ERPA). Mol. Cell Proteomics 5, 1610–1627 (2006).

    Article  CAS  Google Scholar 

  35. Rotin, D. et al. SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: identification of Tyr992 as the high-affinity binding site for SH2 domains of phospholipase Cγ. EMBO J. 11, 559–567 (1992).

    Article  CAS  Google Scholar 

  36. Vega, Q. C. et al. A site of tyrosine phosphorylation in the C terminus of the epidermal growth factor receptor is required to activate phospholipase C. Mol. Cell Biol. 12, 128–135 (1992).

    Article  CAS  Google Scholar 

  37. Cardone, M. H., Smith, B. L., Song, W., Mochley-Rosen, D. & Mostov, K. E. Phorbol myristate acetate-mediated stimulation of transcytosis and apical recycling in MDCK cells. J. Cell Biol. 124, 717–727 (1994).

    Article  CAS  Google Scholar 

  38. Cardone, M. H. et al. Signal transduction by the polymeric immunoglobulin receptor suggests a role in regulation of receptor transcytosis. J. Cell Biol. 133, 997–1005 (1996).

    Article  CAS  Google Scholar 

  39. McKay, M. M. & Morrison, D. K. Integrating signals from RTKs to ERK/MAPK. Oncogene 26, 3113–3121 (2007).

    Article  CAS  Google Scholar 

  40. Robertson, S. E. et al. Extracellular signal-regulated kinase regulates clathrin-independent endosomal trafficking. Mol. Biol. Cell 17, 645–657 (2006).

    Article  CAS  Google Scholar 

  41. Rubinfeld, H. & Seger, R. The ERK cascade: a prototype of MAPK signaling. Mol. Biotechnol. 31, 151–174 (2005).

    Article  CAS  Google Scholar 

  42. Pelkmans, L. et al. Genome-wide analysis of human kinases in clathrin- and caveolae/raft-mediated endocytosis. Nature 436, 78–86 (2005).

    Article  CAS  Google Scholar 

  43. Shirane, M. & Nakayama, K. I. Protrudin induces neurite formation by directional membrane trafficking. Science 314, 818–821 (2006).

    Article  CAS  Google Scholar 

  44. Kholodenko, B. N., Hancock, J. F. & Kolch, W. Signalling ballet in space and time. Nat. Rev. Mol. Cell Biol. 11, 414–426 (2010).

    Article  CAS  Google Scholar 

  45. Lecuit, T. & Pilot, F. Developmental control of cell morphogenesis: a focus on membrane growth. Nat. Cell Biol. 5, 103–108 (2003).

    Article  CAS  Google Scholar 

  46. Zhang, K. & Kaufman, R. J. Signaling the unfolded protein response from the endoplasmic reticulum. J. Biol. Chem. 279, 25935–25938 (2004).

    Article  CAS  Google Scholar 

  47. Lamm, M. E. Current concepts in mucosal immunity IV. How epithelial transport of IgA antibodies relates to host defense. Am. J. Physiol. Gastrointest. Liver Physiol. 274, G614–G617 (1998).

    Article  CAS  Google Scholar 

  48. Kaetzel, C. & Mostov, K. E. Immunoglobulin transport and the polymeric immunoglobulin receptor 211–250 (Academic, 2005).

    Google Scholar 

  49. Strugnell, R. A. & Wijburg, O. L. The role of secretory antibodies in infection immunity. Nat. Rev. Microbiol. 8, 656–667 (2010).

    Article  CAS  Google Scholar 

  50. Polson, A. G. et al. Kaposi's sarcoma-associated herpesvirus K-bZIP protein is phosphorylated by cyclin-dependent kinases. J. Virol. 75, 3175–3184 (2001).

    Article  CAS  Google Scholar 

  51. Witucki, L. A. et al. Mutant tyrosine kinases with unnatural nucleotide specificity retain the structure and phospho-acceptor specificity of the wild-type enzyme. Chem. Biol. 9, 25–33 (2002).

    Article  CAS  Google Scholar 

  52. Bishop, A. C. et al. Generation of monospecific nanomolar tyrosine kinase inhibitors via a chemical genetic approach. J. Am. Chem. Soc. 121, 627–631 (1999).

    Article  CAS  Google Scholar 

  53. Duronio, R. J. et al. Protein N-myristoylation in Escherichia coli: reconstitution of a eukaryotic protein modification in bacteria. Proc. Natl Acad. Sci. USA 87, 1506–1510 (1990).

    Article  CAS  Google Scholar 

  54. Franco, M., Chardin, P., Chabre, M. & Paris, S. Myristoylation of ADP-ribosylation factor 1 facilitates nucleotide exchange at physiological Mg2+ levels. J. Biol. Chem. 270, 1337–1341 (1995).

    Article  CAS  Google Scholar 

  55. Sun, G. & Budde, R. J. Expression, purification, and initial characterization of human Yes protein tyrosine kinase from a bacterial expression system. Arch. Biochem. Biophys. 345, 135–142 (1997).

    Article  CAS  Google Scholar 

  56. Lindsay, A. J. & McCaffrey, M. W. The C2 domains of the class I Rab11 family of interacting proteins target recycling vesicles to the plasma membrane. J. Cell Sci. 117, 4365–75 (2004).

    Article  CAS  Google Scholar 

  57. Mostov, K. E., de Bruyn Kops, A. & Deitcher, D. L. Deletion of the cytoplasmic domain of the polymeric immunoglobulin receptor prevents basolateral localization and endocytosis. Cell 47, 359–364 (1986).

    Article  CAS  Google Scholar 

  58. Greulich, H. et al. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med. 2, e313 (2005).

    Article  Google Scholar 

  59. Stegmeier, F., Hu, G., Rickles, R. J., Hannon, G. J. & Elledge, S. J. A lentiviral microRNA-based system for single-copy polymerase II-regulated RNA interference in mammalian cells. Proc. Natl Acad. Sci. USA 102, 13212–13217 (2005).

    Article  CAS  Google Scholar 

  60. Moffat, J. et al. A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen. Cell 124, 1283–1298 (2006).

    Article  CAS  Google Scholar 

  61. Belcher, J. D. et al. Isolation and characterization of three endosomal fractions from the liver of estradiol-treated rats. Proc. Natl Acad. Sci. USA 84, 6785–6789 (1987).

    Article  CAS  Google Scholar 

  62. Ulrich, S. M., Kenski, D. M. & Shokat, K. M. Engineering a 'methionine clamp' into Src family kinases enhances specificity toward unnatural ATP analogues. Biochemistry 42, 7915–7921 (2003).

    Article  CAS  Google Scholar 

  63. O'Brien, L. E. et al. ERK and MMPs sequentially regulate distinct stages of epithelial tubule development. Dev. Cell 7, 21–32 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Mostov lab members and M. von Zastrow for valuable input and critical reading of the manuscript. We thank K. Young and T. Evans for technical assistance. We acknowledge J. Brugge, J. Goldenring, J. Gordon, M. McCaffrey, J. Peppard, M. Sudol, D. C. James, Q. Fan and J. -P. Vaerman for reagents. This work was supported by NIDDK UCSF Liver Center Pilot Project to the Molecular Structure Core of the Liver Center at UCSF (NIH P30 DK026743; awarded to T.S.), a Susan G Komen Foundation Fellowship (to D.M.B.), a DOD Lung Cancer Concept Award (to A.D.), NIH NCRR 01614 (to A.L.B.), NIH R01EB001987 (to K.M.S.), and R01AI25144, R01DK083330 and R01DK074398 (to K.E.M.).

Author information

Author notes

  1. David M. Bryant and Frédéric Luton: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy, University of California, San Francisco, 94158-2517, CA, USA

    Tao Su, David M. Bryant, Frédéric Luton, Marcel Vergés, Anirban Datta, Dennis J. Eastburn & Keith E. Mostov

  2. Biochemistry and Biophysics, University of California, San Francisco, 94158-2517, CA, USA

    Tao Su, David M. Bryant, Frédéric Luton, Marcel Vergés, Anirban Datta, Dennis J. Eastburn & Keith E. Mostov

  3. Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia-Antipolis, CNRS-UMR6097, 06560, Sophia-Antipolis, France

    Frédéric Luton

  4. Cardiovascular Genetics Centre, IdIBGi - University of Girona, 17003, Girona, Spain

    Marcel Vergés

  5. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94158-2280, CA, USA

    Scott M. Ulrich & Kevan M. Shokat

  6. Department of Chemistry, Ithaca College, Ithaca, 14850, NY, USA

    Scott M. Ulrich

  7. Department of Pharmaceutical Chemistry, University of California, San Francisco, 94158-2517, CA, USA

    Kirk C. Hansen & Alma L. Burlingame

  8. Proteomics Core, University of Colorado Health Sciences Centre, Aurora, 80045, CO, USA

    Kirk C. Hansen

Authors
  1. Tao Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David M. Bryant
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frédéric Luton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marcel Vergés
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Scott M. Ulrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kirk C. Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anirban Datta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dennis J. Eastburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alma L. Burlingame
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kevan M. Shokat
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Keith E. Mostov
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.S., D.M.B., F.L. and K.E.M. designed and analysed the experiments. T.S., D.M.B., M.V. and K.C.H. performed the experiments. A.D., D.J.E, S.M.U., K.M.S. and A.L.B. provided reagents. T.S., D.M.B. and K.E.M. wrote the manuscript. D.M.B. and K.E.M. supervised the project.

Corresponding author

Correspondence to Keith E. Mostov.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 1345 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Su, T., Bryant, D., Luton, F. et al. A kinase cascade leading to Rab11-FIP5 controls transcytosis of the polymeric immunoglobulin receptor. Nat Cell Biol 12, 1143–1153 (2010). https://doi.org/10.1038/ncb2118

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb2118

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