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:

Cables links Robo-bound Abl kinase to N-cadherin-bound β-catenin to mediate Slit-induced modulation of adhesion and transcription

Nature Cell Biology volume 9, pages 883–892 (2007)Cite this article

Abstract

Binding of the secreted axon guidance cue Slit to its Robo receptor results in inactivation of the neural, calcium-dependent cell–cell adhesion molecule N-cadherin, providing a rapid epigenetic mechanism for integrating guidance and adhesion information. This requires the formation of a multimolecular complex containing Robo, Abl tyrosine kinase and N-cadherin. Here we show that on binding of Slit to Robo, the adaptor protein Cables is recruited to Robo-associated Abl and forms a multimeric complex by binding directly to N-cadherin-associated β-catenin. Complex formation results in Abl-mediated phosphorylation of β-catenin on tyrosine 489, leading to a decrease in its affinity for N-cadherin, loss of N-cadherin function, and targeting of phospho-Y489-β-catenin to the nucleus. Nuclear β-catenin combines with the transcription factor Tcf/Lef and activates transcription. Thus, Slit-induced formation of the Robo–N-cadherin complex results in a rapid loss of cadherin-mediated adhesion and has more lasting effects on gene transcription.

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: Cables is incorporated into the Abl–N-cadherin complex on treatment of cells with Slit.
Figure 2: A cell-permeable peptide mimetic that prevents interaction between Cables and Cdk5 prevents the effect of Slit on N-cadherin function.
Figure 3: Cables interacts directly with β-catenin.
Figure 4: Decrease in Cables expression restores interaction between N-cadherin and β-catenin.
Figure 5: Abl phosphorylates β-catenin on tyrosine 489.
Figure 6: β-Catenin phosphorylated on tyrosine 489 is shuttled to the nucleus.
Figure 7: Nuclear phospho-Y489-β-catenin activates transcription and interacts with Tcf/Lef.
Figure 8: Model depicting the formation of the Slit-induced Robo/Abl–N-cadherin/β-catenin complex.

Similar content being viewed by others

References

  1. Faissner, A. & Steindler, D. Boundaries and inhibitory molecules in developing neural tissues. Glia 13, 233–254 (1995).

    Article  CAS  Google Scholar 

  2. Margolis, R. U. & Margolis, R. K. Chondroitin sulfate proteoglycans as mediators of axon growth and pathfinding. Cell Tissue Res. 290, 343–348 (1997).

    Article  CAS  Google Scholar 

  3. Brose, K. et al. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96, 795–806 (1999).

    Article  CAS  Google Scholar 

  4. Balsamo, J., Ernst, H., Zanin, M. K. B., Hoffman, S. & Lilien, J. The interaction of the retina cell surface N-acetylgalactosaminylphosphotransferase with an endogenous proteoglycan ligand results in inhibition of cadherin-mediated adhesion. J. Cell Biol. 129, 1391–1403 (1995).

    Article  CAS  Google Scholar 

  5. Balsamo, J. et al. Regulated binding of PTP1B-like phosphatase to N-cadherin: control of cadherin-mediated adhesion by dephosphorylation of β-catenin. J. Cell Biol. 134, 801–813 (1996).

    Article  CAS  Google Scholar 

  6. Li, H., Leung, T.-C., Hoffman, S., Balsamo, J. & Lilien, J. Coordinate regulation of cadherin and integrin function by the chondroitin sulfate proteoglycan neurocan. J. Cell Biol. 149, 1275–1288 (2000).

    Article  CAS  Google Scholar 

  7. Rhee, J. et al. Activation of the repulsive receptor Roundabout inhibits N-cadherin-mediated cell adhesion. Nature Cell Biol. 4, 798–805 (2002).

    Article  CAS  Google Scholar 

  8. Lilien, J., Balsamo, J., Arregui, C. & Xu, G. Turn-off, drop-out: Functional state switching of cadherins. Dev. Dyn. 224, 18–29 (2002).

    Article  CAS  Google Scholar 

  9. Arregui, C., Pathre, P., Lilien, J. & Balsamo, J. The nonreceptor tyrosine kinase fer mediates cross-talk between N-cadherin and β1-integrins. J. Cell Biol. 149, 1263–1274 (2000).

    Article  CAS  Google Scholar 

  10. Brose, K. & Tessier-Lavigne, M. Slit proteins: key regulators of axon guidance, axonal branching, and cell migration. Curr. Opin. Neurobiol. 10, 95–102 (2000).

    Article  CAS  Google Scholar 

  11. Kidd, T. et al. Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92, 205–215 (1998).

    Article  CAS  Google Scholar 

  12. Ringstedt, T. et al. Slit inhibition of retinal axon growth and its role in retinal axon pathfinding and innervation patterns in the diencephalon. J. Neurosci. 20, 4983–4991 (2000).

    Article  CAS  Google Scholar 

  13. Jin, Z. et al. Irx4-mediated regulation of Slit1 expression contributes to the definition of early axonal paths inside the retina. Development 130, 1037–1048 (2003).

    Article  CAS  Google Scholar 

  14. Thompson, H., Camand, O., Barker, D. & Erskine, L. Slit proteins regulate distinct aspects of retinal ganglion cell axon guidance within the dorsal and ventral retina. J. Neurosci. 26, 8082–8091 (2006).

    Article  CAS  Google Scholar 

  15. Bashaw, G. J., Kidd, T., Murray, D., Pawson, T. & Goodman, C. S. Repulsive axon guidance: Abelson and Enabled play opposing roles downstream of the roundabout receptor. Cell 101, 703–715 (2000).

    Article  CAS  Google Scholar 

  16. Zukerberg, L. R. et al. Cables links cdk5 and c-Abl and facilitates cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron 26, 633–646 (2000).

    Article  CAS  Google Scholar 

  17. Tsai, L.-H., Dalalle, I., Caviness, V. S. Jr, Chae, T. & Harlow, E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371, 419–423 (1994).

    Article  CAS  Google Scholar 

  18. Lew, J. et al. A brain-specific activator of cyclin-dependent kinase 5. Nature 371, 423–426 (1994).

    Article  CAS  Google Scholar 

  19. Patrick, G. N. et al. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402, 615–622 (1999).

    Article  CAS  Google Scholar 

  20. Kwon, Y. T., Gupta, A., Zhou, Y., Nikolic, M. & Tsai, L.-H. Regulation of N-cadherin-mediated adhesion by the p35-Cdk5 kinase. Curr. Biol. 10, 363–372 (2000).

    Article  CAS  Google Scholar 

  21. Kesavapany, S. et al. p35/cdk5 binds and phosphorylates β-catenin and regulates β-catenin/presenilin-1 interaction. Eur. J. Neurosci. 13, 241–247 (2001).

    CAS  PubMed  Google Scholar 

  22. Stein, E. & Tessier-Lavigne, M. Hierarchical organization of guidance receptors: Silencing of netrin attraction by Slit through a Robo–DCC receptor complex. Science 291, 1928–1938 (2001).

    Article  CAS  Google Scholar 

  23. Wu, J. J., Afar, D. E., Phan, H., Witte, O. N. & Lam, K. S. Recognition of multiple substrate motifs by the c-ABL protein tyrosine kinase. Comb. Chem. High Throughput Screen 5, 83–91 (2002).

    Article  CAS  Google Scholar 

  24. Xu, G., Arregui, C., Lilien, J. & Balsamo, J. PTP1B modulates the association of β-catenin with N-cadherin through binding to an adjacent and partially overlapping target site. J. Biol. Chem. 277, 49989–49997 (2002).

    Article  CAS  Google Scholar 

  25. Xu, G. et al. Continuous association of cadherin with β-catenin requires phosphorylation of PTP1B by Fer. J. Cell Sci. 117, 3207–3219 (2004).

    Article  CAS  Google Scholar 

  26. Lilien, J. & Balsamo, J. Rapid reversible changes in cadherin function regulated by tyrosine phosphorylation of β-catenin. Curr. Opin. Cell Biol. 17, 459–465 (2005).

    Article  CAS  Google Scholar 

  27. Roura, S., Miravet, S., Piedra, J., de Herreros, A. G. & Dunach, M. Regulation of E-cadherin/catenin association by tyrosine phosphorylation. J. Biol. Chem. 274, 36734–36740 (1999).

    Article  CAS  Google Scholar 

  28. Miravet, S. et al. Tyrosine phosphorylation of plakoglobin causes contrary effects on its association with desmosomes and adherens junction components and modulates β-catenin-mediated transcription. Mol. Cell. Biol. 23, 7391–7402 (2003).

    Article  CAS  Google Scholar 

  29. Huber, A. H. & Weis, W. I. The structure of the β-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by β-catenin. Cell 105, 391–402 (2001).

    Article  CAS  Google Scholar 

  30. Gao, C. Y., Stepp, M. A., Fariss, R. & Zelenka, P. Cdk5 regulates activation and localization of Src during corneal epithelial wound closure. J. Cell Sci. 117, 4089–4098 (2004).

    Article  CAS  Google Scholar 

  31. Hsouna, A., Kim, Y. S. & VanBerkum, M. F. Abelson tyrosine kinase is required to transduce midline repulsive cues. J. Neurobiol. 57, 15–30 (2003).

    Article  CAS  Google Scholar 

  32. Piedra, J. et al. p120 catenin-associated Fer and Fyn tyrosine kinases regulate β-catenin Tyr-142 phosphorylation and β-catenin–α-catenin interaction. Mol. Cell Biol. 23, 2287–2297 (2003).

    Article  CAS  Google Scholar 

  33. Brembeck, F. H. et al. Essential role of BCL9-2 in the switch between β-catenin's adhesive and transcriptional functions. Genes Dev. 18, 2225–2230 (2004).

    Article  CAS  Google Scholar 

  34. Brembeck, F. H., Rosario, M. & Birchmeier, W. Balancing cell adhesion and Wnt signaling, the key role of β-catenin. Curr. Opin. Genet. Dev. 16, 51–59 (2006).

    Article  CAS  Google Scholar 

  35. Monga, S. P. et al. Hepatocyte growth factor induces Wnt-independent nuclear translocation of β-catenin after Met-β-catenin dissociation in hepatocytes. Cancer Res. 62, 2064–2071 (2002).

    CAS  PubMed  Google Scholar 

  36. Sampietro, J. et al. Crystal structure of a β-catenin/BCL9/Tcf4 complex. Mol. Cell 24, 293–300 (2006).

    Article  CAS  Google Scholar 

  37. Hoffmans, R. & Basler, K. BCL9-2 binds Arm/β-catenin in a Tyr142-independent manner and requires Pygopus for its function in Wg/Wnt signaling. Mech. Dev. 124, 59–67 (2007).

    Article  CAS  Google Scholar 

  38. Kikuchi, A., Kishida, S. & Yamamoto, H. Regulation of Wnt signaling by protein-protein interaction and post-translational modifications. Exp. Mol. Med. 28, 1–10 (2006).

    Article  Google Scholar 

  39. Behrens, J. & Lustig, B. The Wnt connection to tumorigenesis. Int. J. Dev. Biol. 8, 477–487 (2004).

    Article  Google Scholar 

  40. Gottardi, C. J. & Gumbiner, B. M. Distinct molecular forms of β-catenin are targeted to adhesive or transcriptional complexes. J. Cell Biol. 167, 339–349 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Willard for expert technical assistance. This work was supported by a grant from the NIH (EY13363).

Author information

Author notes

  1. Jinseol Rhee

    Present address: Current address: Howard Hughes Medical Institute, Department of Physiology, University of California, 1550 Fourth Street, San Francisco, California 94143-2611, USA.,

Authors and Affiliations

  1. Department of Biological Sciences, The University of Iowa, Iowa City, 52242-1324, Iowa, USA

    Jinseol Rhee, Tim Buchan, Jack Lilien & Janne Balsamo

  2. Department of Pathology, Massachusetts General Hospital, Boston, 02115, Massachusetts, USA

    Lawrence Zukerberg

Authors
  1. Jinseol Rhee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tim Buchan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lawrence Zukerberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jack Lilien
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Janne Balsamo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.R. performed the experiments revealing the involvement of Cables, Cdk5 and p35. L.Z. provided Cables and Cdk5 cDNAs and all siRNA constructs. T.B. prepared stable cell lines expressing siRNAs and performed the transcriptional analyses. J.B. and J.L. provided intellectual guidance, resources, support and many critical experiments (J.B.).

Corresponding author

Correspondence to Jack Lilien.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures 1, 2, 3, 4, 7 and Supplementary Data (PDF 569 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rhee, J., Buchan, T., Zukerberg, L. et al. Cables links Robo-bound Abl kinase to N-cadherin-bound β-catenin to mediate Slit-induced modulation of adhesion and transcription. Nat Cell Biol 9, 883–892 (2007). https://doi.org/10.1038/ncb1614

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1614

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