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Regulation of protein tyrosine phosphatase 1B by sumoylation

Nature Cell Biology volume 9, pages 80–85 (2007)Cite this article

Abstract

Protein-tyrosine phosphatase 1B (PTP1B) is an ubiquitously expressed enzyme that negatively regulates growth-factor signalling and cell proliferation by binding to and dephosphorylating key receptor tyrosine kinases, such as the insulin receptor1. It is unclear how the activity of PTP1B is regulated. Using a yeast two-hybrid assay, a protein inhibitor of activated STAT1 (PIAS1)2 was isolated as a PTP1B-interacting protein. Here, we show that PIAS1, which functions as a small ubiquitin-like modifier (SUMO) E3 ligase, associates with PTP1B in mammalian fibroblasts and catalyses sumoylation of PTP1B. Sumoylation of PTP1B reduces its catalytic activity and inhibits the negative effect of PTP1B on insulin receptor signalling and on transformation by the oncogene v-crk. Insulin-stimulated sumoylation of endogenous PTP1B results in a transient downregulation of the enzyme; this event does not occur when the endogenous enzyme is replaced with a sumoylation-resistant mutant of PTP1B. These results suggest that sumoylation, which has been implicated primarily in processes in the nucleus and nuclear pore, also modulates a key enzyme–substrate signalling complex that regulates metabolism and cell proliferation.

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Figure 1: PTP1B undergoes sumoylation in cells.
Figure 2: FLIM analysis of PTP1B and SUMO-1.
Figure 3: Mapping sumoylation sites on PTP1B.
Figure 4: Sumoylation of PTP1B reduces its catalytic activity.
Figure 5: Regulation of PTP1B through sumoylation.

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Acknowledgements

We thank V. Guacci, A. Kikuchi, S. Michaelis, J. Palvimo, M. White and H. Yokosawa for their gifts of reagents, and D. Dadke for her assistance. This work was supported by grants from the National Institutes of Health (B.G.N., K.S. and J.C), an endowment fund from the Richard Dimbleby Cancer Fund to King's College London (T.N.), a National Cancer Institute CORE grant to the Fox Chase Cancer Center, and an appropriation from the Commonwealth of Pennsylvania. The multiphoton FLIM system was built with support from both the Medical Research Council Co-Operative Group grant (G0100152 ID 56891) and an UK Research Councils Basic Technology Research Programme grant (GR/R87901/01).

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Author notes

  1. Shrikrishna Dadke

    Present address: Diabetes Research Program, Stem Cell Research Center, 9th Floor, Manipal Hospital, Airport Road, Bangalore, 560017, Karnataka, India

  2. Fawaz Haj

    Present address: Nutrition Department, University of California at Davis, 3135 Meyer Hall, One Shields Avenue, Davis, CA 95616, USA

  3. Shrikrishna Dadke and Sophie Cotteret: These authors contributed equally to this work.

Authors and Affiliations

  1. Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, 19111, PA, USA

    Shrikrishna Dadke, Sophie Cotteret, Shu-Chin Yip, Zahara M. Jaffer & Jonathan Chernoff

  2. Department of Medicine, Cancer Biology Program, Beth Israel Deaconess Medical Center, New Research Building, Rm # 1030, 77 Avenue Louis Pasteur, Boston, 02115, MA, USA

    Fawaz Haj & Benjamin G. Neel

  3. Wistar Institute, 3601 Spruce St., Philadelphia, 19104, PA, USA

    Alexey Ivanov & Frank Rauscher III

  4. Division of Hematology-Oncology, University of California Los Angeles, 11-934 Factor Building, 10833 Le Conte Avenue, Los Angeles, 90095, CA, USA

    Ke Shuai

  5. Randall Division of Cell and Molecular Biophysics, Guy's Campus, King's College, London, SE1 1UL, UK

    Tony Ng

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Contributions

S.D. and J.C. conceived the project and prepared most of the manuscript. S.D., S.C., S.-C.Y. and Z.M.J. performed the biochemical and cellular analyses. T.N. carried out the FLIM experiments shown in Fig. 2. F.H., A.I., F.R., K.S. and B.G.N. provided key reagents, cell lines and/or advice.

Corresponding author

Correspondence to Jonathan Chernoff.

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The authors declare no competing financial interests.

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Supplementary Information

Supplementary figures S1, S2, S3 and S4 (PDF 265 kb)

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Dadke, S., Cotteret, S., Yip, SC. et al. Regulation of protein tyrosine phosphatase 1B by sumoylation. Nat Cell Biol 9, 80–85 (2007). https://doi.org/10.1038/ncb1522

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