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.

  • Brief Communication
  • Published:

Regulation of PTP1B activation through disruption of redox-complex formation

Abstract

We have identified a molecular interaction between the reversibly oxidized form of protein tyrosine phosphatase 1B (PTP1B) and 14-3-3ζ that regulates PTP1B activity. Destabilizing the transient interaction between 14-3-3ζ and PTP1B prevented PTP1B inactivation by reactive oxygen species and decreased epidermal growth factor receptor phosphorylation. Our data suggest that destabilizing the interaction between 14-3-3ζ and the reversibly oxidized and inactive form of PTP1B may establish a path to PTP1B activation in cells.

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

Fig. 1: The exposed pTyr recognition loop of PTP1B-OX interacts with 14-3-3ζ.
Fig. 2: Destabilizing the association between 14-3-3ζ and PTP1B-OX prevents PTP1B inactivation and decreases EGFR phosphorylation.

Similar content being viewed by others

Data availability

The structures of reduced PTP1B (PDB code: 2HNQ) and PTP1B-OX (PDB code: 1OEM) were used for the accessible surface area calculation. The MS data in Supplementary Tables 1 and 2 will be made available in the PRoteomics IDEntifications database.

References

  1. Finkel, T. Signal transduction by reactive oxygen species. J. Cell Biol. 194, 7–15 (2011).

    Article  CAS  Google Scholar 

  2. Ostman, A., Frijhoff, J., Sandin, A. & Böhmer, F. D. Regulation of protein tyrosine phosphatases by reversible oxidation. J. Biochem. 150, 345–356 (2011).

    Article  Google Scholar 

  3. Tonks, N. K. Protein tyrosine phosphatases: from genes, to function, to disease. Nat. Rev. Mol. Cell Biol. 7, 833–846 (2006).

    Article  CAS  Google Scholar 

  4. Karisch, R. et al. Global proteomic assessment of the classical protein-tyrosine phosphatome and “Redoxome”. Cell 146, 826–840 (2011).

    Article  CAS  Google Scholar 

  5. Brown, D. I. & Griendling, K. K. Regulation of Signal Transduction by Reactive Oxygen Species in the Cardiovascular System. Circ. Res. 116, 531–549 (2015).

    Article  CAS  Google Scholar 

  6. Tonks, N. K. PTP1B: from the sidelines to the front lines! FEBS Lett. 546, 140–148 (2003).

    Article  CAS  Google Scholar 

  7. Feldhammer, M., Uetani, N., Miranda-Saavedra, D. & Tremblay, M. L. PTP1B: a simple enzyme for a complex world. Crit. Rev. Biochem. Mol. Biol. 48, 430–445 (2013).

    Article  CAS  Google Scholar 

  8. Salmeen, A. et al. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 423, 769–773 (2003).

    Article  CAS  Google Scholar 

  9. van Montfort, R. L., Congreve, M., Tisi, D., Carr, R. & Jhoti, H. Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. Nature 423, 773–777 (2003).

    Article  Google Scholar 

  10. Haque, A., Andersen, J. N., Salmeen, A., Barford, D. & Tonks, N. K. Conformation-sensing antibodies stabilize the oxidized form of PTP1B and inhibit its phosphatase activity. Cell 147, 185–198 (2011).

    Article  CAS  Google Scholar 

  11. Krishnan, N. et al. Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development. Nat. Commun. 9, 283 (2018).

    Article  Google Scholar 

  12. Zhao, J., Meyerkord, C. L., Du, Y., Khuri, F. R. & Fu, H. 14-3-3 proteins as potential therapeutic targets. Semin. Cell Dev. Biol. 22, 705–712 (2011).

    Article  Google Scholar 

  13. Reinhardt, H. C. & Yaffe, M. B. Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response. Nat. Rev. Mol. Cell Biol. 14, 563–580 (2013).

    Article  CAS  Google Scholar 

  14. Andersen, J. N. et al. Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol. Cell Biol. 21, 7117–7136 (2001).

    Article  CAS  Google Scholar 

  15. Lee, S. R., Kwon, K. S., Kim, S. R. & Rhee, S. G. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J. Biol. Chem. 273, 15366–15372 (1998).

    Article  CAS  Google Scholar 

  16. Boivin, B., Zhang, S., Arbiser, J. L., Zhang, Z. Y. & Tonks, N. K. A modified cysteinyl-labeling assay reveals reversible oxidation of protein tyrosine phosphatases in angiomyolipoma cells. Proc. Natl Acad. Sci. USA 105, 9959–9964 (2008).

    Article  CAS  Google Scholar 

  17. Boivin, B., Yang, M. & Tonks, N. K. Targeting the reversibly oxidized protein tyrosine phosphatase superfamily. Sci. Signal. 3, pl2 (2010).

    Article  Google Scholar 

  18. Wang, B. et al. Isolation of high-affinity peptide antagonists of 14-3-3 proteins by phage display. Biochemistry 38, 12499–12504 (1999).

    Article  CAS  Google Scholar 

  19. Ravichandran, L. V., Chen, H., Li, Y. & Quon, M. J. Phosphorylation of PTP1B at Ser(50) by Akt impairs its ability to dephosphorylate the insulin receptor. Mol. Endocrinol. 15, 1768–1780 (2001).

    Article  CAS  Google Scholar 

  20. Yang, L. et al. Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. Cancer Res. 64, 4394–4399 (2004).

    Article  CAS  Google Scholar 

  21. Milarski, K. L. et al. Sequence specificity in recognition of the epidermal growth factor receptor by protein tyrosine phosphatase 1B. J. Biol. Chem. 268, 23634–23639 (1993).

    CAS  PubMed  Google Scholar 

  22. Biscardi, J. S. et al. c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J. Biol. Chem. 274, 8335–8343 (1999).

    Article  CAS  Google Scholar 

  23. Lessard, L., Stuible, M. & Tremblay, M. L. The two faces of PTP1B in cancer. Biochim. Biophys. Acta 1804, 613–619 (2010).

    Article  CAS  Google Scholar 

  24. Dagnell, M. et al. Selective activation of oxidized PTP1B by the thioredoxin system modulates PDGF-β receptor tyrosine kinase signaling. Proc. Natl Acad. Sci. USA 110, 13398–13403 (2013).

    Article  CAS  Google Scholar 

  25. Parsons, Z. D. & Gates, K. S. Thiol-dependent recovery of catalytic activity from oxidized protein tyrosine phosphatases. Biochemistry 52, 6412–6423 (2013).

    Article  CAS  Google Scholar 

  26. Zougman, A., Selby, P. J. & Banks, R. E. Suspension trapping (STrap) sample preparation method for bottom‐up proteomics analysis. Proteomics 14, 1006–11010 (2014).

    Article  CAS  Google Scholar 

  27. Ross, P. L. et al. Multiplexed protein quantitation in Saccharomyces cerevisiae using amine-reactive isobaric tagging reagents. Mol. Cell. Proteom. 3, 1154–1169 (2004).

    Article  CAS  Google Scholar 

  28. Perkins, D. N., Pappin, D. J., Creasy, D. M. & Cottrell, J. S. Probability-based protein identification by searching sequence databases using mass spectrometry data. Electrophoresis 20, 3551–3567 (1999).

    Article  CAS  Google Scholar 

  29. Collaborative Computational Project, N. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994).

    Article  Google Scholar 

Download references

Acknowledgements

We thank H. Fu for providing the 14-3-3ζ plasmid. This research was supported by the National Institutes of Health grant no. HL138605 and the American Heart Association grant no. 17GRNT33700265 to B.B. and National Institutes of Health grant no. GM55989 to N.K.T. B.B. is also grateful for support from the following foundations: the Heart and Stroke Foundation of Canada and SUNY Research Foundation. B.B. is an FRQS Research Scholar and A.B. was the recipient of a scholarship from the FRQS.

Author information

Authors and Affiliations

Authors

Contributions

A.D.L., A.B., S.M.C., A.K., G.C., S.H.M.R. and B.B. performed experiments and analyzed data. K.D.R. and D.J.P. acquired and analyzed MS data. S.J.K. performed structural analysis and modeling. F.Z. and R.J.L. acquired and analyzed SPR data. N.K.T. and B.B. wrote the manuscript.

Corresponding author

Correspondence to Benoit Boivin.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2 and Figs. 1–21.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Londhe, A.D., Bergeron, A., Curley, S.M. et al. Regulation of PTP1B activation through disruption of redox-complex formation. Nat Chem Biol 16, 122–125 (2020). https://doi.org/10.1038/s41589-019-0433-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41589-019-0433-0

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research