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The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis

Nature Medicine volume 12, pages 549–556 (2006)Cite this article

Abstract

The protein tyrosine phosphatase SHP-1 is a well-known inhibitor of activation-promoting signaling cascades in hematopoietic cells but its potential role in insulin target tissues is unknown. Here we show that Ptpn6me-v/me-v (also known as viable motheaten) mice bearing a functionally deficient SHP-1 protein are markedly glucose tolerant and insulin sensitive as compared to wild-type littermates, as a result of enhanced insulin receptor signaling to IRS-PI3K-Akt in liver and muscle. Downregulation of SHP-1 activity in liver of normal mice by adenoviral expression of a catalytically inert mutant of SHP-1, or after small hairpin RNA–mediated SHP-1 silencing, further confirmed this phenotype. Tyrosine phosphorylation of CEACAM1, a modulator of hepatic insulin clearance, and clearance of serum [125I]-insulin were markedly increased in SHP-1–deficient mice or SHP-1–deficient hepatic cells in vitro. These findings show a novel role for SHP-1 in the regulation of glucose homeostasis through modulation of insulin signaling in liver and muscle as well as hepatic insulin clearance.

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Figure 1: SHP-1 is expressed in skeletal muscle and liver.
Figure 2: Metabolic phenotyping of wild-type and SHP-1–deficient Ptpn6me-v/me-v mice.
Figure 3: Insulin signaling to PI3K-Akt in muscle and liver of wild-type and Ptpn6me-v/me-v mice.
Figure 4: Effects of liver-specific overexpression of DNSHP-1 and knockdown of SHP-1 by shRNA-mediated gene silencing on glucose metabolism and insulin signaling.
Figure 5: SHP-1 regulates phosphorylation of CEACAM1 in liver and modulates hepatic insulin clearance.
Figure 6: SHP-1 binds to and dephosphorylates the insulin receptor, CEACAM1 and p85-PI3K in mouse liver.

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Acknowledgements

This work was supported by grants from the Canadian Diabetes Association (to A.M.) and Canadian Institutes for Health Research (CIHR) (to A.M., K.A.S. and N.B.). Part of this study was also conducted at the US National Institutes of Health–Yale Mouse Metabolic Phenotyping Center and supported by grants from the United States Public Health Service (U24 DK-59635 to G.I.S. and J.K.K.) and the American Diabetes Association (7-01-JF-05 to J.K.K.). A.M. is the recipient of a CIHR Investigator Award. K.A.S. is a CIHR Senior Scientist and a McLaughlin Centre for Molecular Medicine Scientist. M.O. is a CIHR investigator and a Burroughs Wellcome Fund Fellow. G.I.S. is an investigator of Howard Hughes Medical Institute and the recipient of a Distinguished Clinical Scientist Award from the American Diabetes Association. N.B. is a senior researcher from the Fonds de la recherche en Santé du Québec. M.-J.D. and S.B. were supported by studentships from the Fonds de la recherche en Santé du Québec and the Canadian Diabetes Association. We thank B. Marcotte, S. Brûlé, P. Dallaire, N. Lefort, S. Fortier, V. Rampersad, J. Blanchette and T. Higashimori for technical assistance. We also thank A. Simard and S. Rivest for their help with immunofluorescence microscopy, M.L. Tremblay (McGill Univ.) for providing wild-type and mutant forms of GST-PTP1B and GST–PTP-PEST, and A. Veillette for the SHP-1–specific antibody.

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Author notes

  1. Marie-Julie Dubois and Sébastien Bergeron: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy-Physiology and Lipid Research Unit, Laval University Hospital Research Center, 2705 Laurier Boulevard, Québec, Québec, G1V 4G2, Canada

    Marie-Julie Dubois, Sébastien Bergeron, Luce Dombrowski, Mylène Perreault & André Marette

  2. Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale Mouse Metabolic Phenotyping Center, Yale University School of Medicine, The Anlyan Center, 300 Cedar Street, New Haven, 06520, Connecticut, USA

    Hyo-Jeong Kim, Gerald I Shulman & Jason K Kim

  3. Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, 17033, Pennsylvania, USA

    Hyo-Jeong Kim

  4. McGill Cancer Centre, McGill University, 3655 Promenade Sir-William-Osler, Montreal, H3G 1Y6, Quebec, Canada

    Bénédicte Fournès & Nicole Beauchemin

  5. Department of Pediatrics, Laval University Hospital Research Center, 2705 Laurier Boulevard, Québec, G1V 4G2, Québec, Canada

    Robert Faure

  6. Departments of Experimental Medicine, Microbiology and Immunology, McGill University, 3775 University Street, Montreal, H3A 2B4, Quebec, Canada

    Martin Olivier

  7. Howard Hughes Medical Institute, University of Toronto, Mount Sinai Hospital Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Gerald I Shulman

  8. Departments of Medicine and Immunology, University of Toronto, Mount Sinai Hospital Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Katherine A Siminovitch

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Correspondence to André Marette.

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Supplementary information

Supplementary Fig. 1

SHP-1 immunoreactivity in liver and skeletal muscle of wild-type and Ptpn6me/me mice. (PDF 90 kb)

Supplementary Fig. 2

Effect of wortmannin on 2-DG uptake by soleus and EDL muscles of wild-type and SHP-1–deficient Ptpn6me-v/me-v mice. (PDF 50 kb)

Supplementary Fig. 3

Insulin signaling in muscle and liver of wild-type and Ptpn6me-v/me-v or lacZ- and DNSHP-1–transduced mice. (PDF 104 kb)

Supplementary Fig. 4

PTEN tyrosine phosphorylation in liver of animal models of SHP-1 deficiency. (PDF 78 kb)

Supplementary Fig. 5

In vivo transduction of liver after systemic delivery of adenovirally encoded GFP. (PDF 352 kb)

Supplementary Table 1

Physiological parameters of wild-type and SHP-1–deficient mice. (PDF 21 kb)

Supplementary Table 2

Quantification of changes in insulin-stimulated tyrosine phosphorylation of insulin signaling problems in tissues of Ptpn6me-v/me-v and DNSHP-1–transduced mice. (PDF 19 kb)

Supplementary Methods (PDF 25 kb)

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Dubois, MJ., Bergeron, S., Kim, HJ. et al. The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis. Nat Med 12, 549–556 (2006). https://doi.org/10.1038/nm1397

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