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:

Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5

Nature Cell Biology volume 8, pages 435–445 (2006)Cite this article

Abstract

Nutrients and growth hormones promote insulin production and the proliferation of pancreatic β-cells. An imbalance between ever-increasing metabolic demands and insulin output causes diabetes. Recent evidence indicates that β-cells enhance insulin gene expression depending on their secretory activity. This signalling pathway involves a catalytically inactive receptor tyrosine phosphatase, ICA512, whose cytoplasmic tail is cleaved on glucose-stimulated exocytosis of insulin secretory granules and then moves into the nucleus, where it upregulates insulin transcription. Here, we show that the cleaved cytosolic fragment of ICA512 enhances the transcription of secretory granule genes (including its own gene) by binding to tyrosine phosphorylated signal transducers and activators of transcription (STAT) 5 and preventing its dephosphorylation. Sumoylation of ICA512 by the E3 SUMO ligase PIASy, in turn, may reverse this process by decreasing the binding of ICA512 to STAT5. These findings illustrate how the exocytosis of secretory granules, through a retrograde pathway that sustains STAT activity, converges with growth hormone signalling to induce adaptive changes in β-cells in response to metabolic demands.

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: ICA512 enhances the transcription of secretory granule genes.
Figure 2: ICA512 enhances the nuclear levels of STATs.
Figure 3: ICA512 enhances the nuclear levels of PY-STAT5.
Figure 4: ICA512 binds to STAT5b and prevents its dephosphorylation.
Figure 5: ICA512 increases STAT5b activity.
Figure 6: ICA512-mediated binding of PIASy to STAT5.
Figure 7: Sumoylation of ICA512 regulates its binding to STAT5.
Figure 8: STAT5b promotes the transcription of ICA512.

Similar content being viewed by others

References

  1. Goodge, K. A. & Hutton, J. C. Translational regulation of proinsulin biosynthesis and proinsulin conversion in the pancreatic β-cell. Semin. Cell. Dev. Biol. 11, 235–242 (2000).

    Article  CAS  Google Scholar 

  2. Welsh, M., Nielsen, D. A., MacKrell, A. J. & Steiner, D. F. Control of insulin gene expression in pancreatic β-cells and in an insulin-producing cell line, RIN-5F cells. II. Regulation of insulin mRNA stability. J. Biol. Chem. 260, 13590–13594 (1985).

    CAS  PubMed  Google Scholar 

  3. Leibiger, I. B., Leibiger, B., Moede, T. P. & Berggren, O. Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Mol. Cell. 1, 933–938 (1998).

    Article  CAS  Google Scholar 

  4. Kennedy, H. J., Rafiq, I., Pouli, A. E. & Rutter, G. A. Glucose enhances insulin promoter activity in MIN6 β-cells independently of changes in intracellular Ca2+ concentration and insulin secretion. Biochem. J. 342, 275–280 (1999).

    Article  CAS  Google Scholar 

  5. Wicksteed, B., Alarcon, C., Briaud, I., Lingohr, M. K. & Rhodes, C. J. Glucose-induced translational control of proinsulin biosynthesis is proportional to preproinsulin mRNA levels in islet β-cells but not regulated via a positive feedback of secreted insulin. J. Biol. Chem. 278, 42080–42090 (2003).

    Article  CAS  Google Scholar 

  6. Otani, K. et al. Reduced β-cell mass and altered glucose sensing impair insulin-secretory function in βIRKO mice. Am. J. Physiol. Endocrinol. Metab. 286, E41–E49 (2004).

    Article  CAS  Google Scholar 

  7. Trajkovski, M. et al. Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in β-cells. J. Cell Biol. 167, 1063–1074 (2004).

    Article  CAS  Google Scholar 

  8. Lan, M. S., Lu, J., Goto, Y. & Notkins, A. L. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma. DNA Cell Biol. 13, 505–514 (1994).

    Article  CAS  Google Scholar 

  9. Zahn, T. R., Macmorris, M. A., Dong, W., Day, R. & Hutton, J. C. IDA-1, a Caenorhabditis elegans homolog of the diabetic autoantigens IA-2 and phogrin, is expressed in peptidergic neurons in the worm. J. Comp. Neurol. 429, 127–143 (2001).

    Article  CAS  Google Scholar 

  10. Magistrelli, G., Toma, S. & Isacchi, A. Substitution of two variant residues in the protein tyrosine phosphatase-like PTP35–IA-2 sequence reconstitutes catalytic activity. Biochem. Biophys. Res. Commun. 227, 581–588 (1996).

    Article  CAS  Google Scholar 

  11. Saeki, K. et al. Targeted disruption of the protein tyrosine phosphatase-like molecule IA-2 results in alterations in glucose tolerance tests and insulin secretion. Diabetes 51, 1842–1850 (2002).

    Article  CAS  Google Scholar 

  12. Harashima, S, Clark, A., Christie, M. R. & Notkins, A. L. The dense core transmembrane vesicle protein IA-2 is a regulator of vesicle number and insulin secretion. Proc. Natl Acad. Sci. USA 102, 8704–8709 (2005).

    Article  CAS  Google Scholar 

  13. Solimena, M. et al. ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules. EMBO J. 15, 2102–2114 (1996).

    Article  CAS  Google Scholar 

  14. Hermel, J. M., Dirkx, R. & Solimena, M. Post-translational modifications of ICA512, a receptor tyrosine phosphatase-like protein of secretory granules. Eur. J. Neurosci. 11, 2609–2620 (1999).

    Article  CAS  Google Scholar 

  15. Ort, T. et al. Dephosphorylation of β2-syntrophin and Ca2+–μ-calpain-mediated cleavage of ICA512 upon stimulation of insulin secretion. EMBO J. 20, 4013–4023 (2001).

    Article  CAS  Google Scholar 

  16. Knoch, K. P. et al. Polypyrimidine tract-binding protein promotes insulin secretory granule biogenesis. Nature Cell Biol. 6, 207–214 (2004).

    Article  CAS  Google Scholar 

  17. Knoch, K. P. et al. cAMP-dependent phosphorylation of PTB1 promotes the expression of insulin secretory granule proteins in β-cells. Cell Metab. 3, 123–134 (2006).

    Article  CAS  Google Scholar 

  18. Levy, D. E. & Darnell, J. E. Jr. Stats: transcriptional control and biological impact. Nature Rev. Mol. Cell Biol. 3, 651–662 (2002).

    Article  CAS  Google Scholar 

  19. Nielsen, J. H. et al. Regulation of β-cell mass by hormones and growth factors. Diabetes 50, S25–S29 (2001).

    Article  CAS  Google Scholar 

  20. Brelje, T. C., Stout, L. E., Bhagroo, N. V. & Sorenson, R. L. Distinctive roles for prolactin and growth hormone in the activation of signal transducer and activator of transcription 5 in pancreatic islets of Langerhans. Endocrinology 145, 4162–4175 (2004).

    Article  CAS  Google Scholar 

  21. Weinhaus, A. J., Stout, L. E. & Sorenson, R. L. Glucokinase, hexokinase, glucose transporter 2, and glucose metabolism in islets during pregnancy and prolactin-treated islets in vitro: mechanisms for long term up-regulation of islets. Endocrinology 137, 1640–1649 (1996).

    Article  CAS  Google Scholar 

  22. Friedrichsen, B. N. et al. Signal transducer and activator of transcription 5 activation is sufficient to drive transcriptional induction of cyclin D2 gene and proliferation of rat pancreatic β-cells. Mol. Endocrinol. 17, 945–958 (2003).

    Article  CAS  Google Scholar 

  23. ten Hoeve, J. et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol. Cell. Biol. 22, 5662–5668 (2002).

    Article  CAS  Google Scholar 

  24. Galsgaard, E. D. et al. Identification of a growth hormone-responsive STAT5-binding element in the rat insulin 1 gene. Mol. Endocrinol. 10, 652–660 (1996).

    CAS  PubMed  Google Scholar 

  25. Rodriguez, M. S., Dargemont, C. & Hay, R. T. SUMO-1 conjugation in vivo requires both a consensus modification motif and nuclear targeting. J. Biol. Chem. 276, 12654–12659 (2001).

    Article  CAS  Google Scholar 

  26. Johnson, E. S. & Gupta, A. A. An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 106, 735–744 (2001).

    Article  CAS  Google Scholar 

  27. Melchior, F., Schergaut, M. & Pichler, A. SUMO: ligases, isopeptidases and nuclear pores. Trends Biochem. Sci. 28, 612–618 (2003).

    Article  CAS  Google Scholar 

  28. Uchimura, Y., Nakamura, M., Sugasawa, K., Nakao, M. & Saitoh, H. Overproduction of eukaryotic SUMO-1 and SUMO-2-conjugated proteins in Escherichia coli. Anal. Biochem. 331, 204–206 (2004).

    Article  CAS  Google Scholar 

  29. Sarmiento, M., Zhao, Y., Gordon, S. J. & Zhang, Z. Y. Molecular basis for substrate specificity of protein-tyrosine phosphatase 1B. J. Biol. Chem. 273, 26368–26374 (1998).

    Article  CAS  Google Scholar 

  30. Drake, P. G., Peters, G. H., Andersen, H. S., Hendriks, W. & Møller N. P. A novel strategy for the development of selective active-site inhibitors of the protein tyrosine phosphatase-like proteins islet-cell antigen 512 (IA-2) and phogrin (IA-2β). Biochem. J. 373, 393–401 (2003).

    Article  CAS  Google Scholar 

  31. Berg, K. L., Siminovitch, K. A. & Stanley, R. E. SHP-1 regulation of the p62DOK tyrosine phsophorylation in macrophages. J. Biol. Chem. 274, 35855–35865 (1999).

    Article  CAS  Google Scholar 

  32. Felberg, J. et al. Subdomain X of the kinase domain of Lck binds CD45 and facilitates dephosphorylation. J. Biol. Chem. 279, 3455–3462 (2004).

    Article  CAS  Google Scholar 

  33. Aoki, N. & Matsuda, T. A nuclear protein tyrosine phosphatase TC-PTP is a potential negative regulator of the PRL-mediated signaling pathway: dephosphorylation and deactivation of signal transducer and activator of transcription 5a and 5b by TC-PTP in nucleus. Mol. Endocrinol. 16, 58–69 (2002).

    Article  CAS  Google Scholar 

  34. Chen, Y. et al. Identification of Shp-2 as a Stat5A phosphatase. J. Biol. Chem. 278, 16520–16527 (2003).

    Article  CAS  Google Scholar 

  35. Gu, F. et al. Protein tyrosine phosphatase 1B attenuates growth hormone-mediated JAK2-STAT signaling. Mol. Cell Biol. 23, 3753–3762 (2003).

    Article  CAS  Google Scholar 

  36. Liu, B. et al. Inhibition of Stat1-mediated gene activation by PIAS1. Proc. Natl Acad. Sci. USA 95, 10626–10631 (1998).

    Article  CAS  Google Scholar 

  37. Ungureanu, D. et al. PIAS proteins promote SUMO-1 conjugation to STAT1. Blood 102, 3311–3313 (2003).

    Article  CAS  Google Scholar 

  38. Matsuoka, T., Zhao, L. & Stein, R. The DNA binding activity of the RIPE3b1 transcription factor of insulin appears to be influenced by tyrosine phosphorylation. J. Biol. Chem. 276, 22071–22076 (2001).

    Article  CAS  Google Scholar 

  39. Kishi, A. et al. Sumoylation of Pdx1 is associated with its nuclear localization and insulin gene activation. Am. J. Physiol. Endocrinol. Metab. 284, E830–E840 (2003).

    Article  CAS  Google Scholar 

  40. Drucker, D. J. Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol. Endocrinol. 17, 161–171 (2003).

    Article  CAS  Google Scholar 

  41. Melloul, D., Marshak, S. & Cerasi, E. Regulation of insulin gene transcription. Diabetol. 45, 309–326 (2002).

    Article  CAS  Google Scholar 

  42. Horikawa, Y. et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nature Genet. 26, 163–175 (2000).

    Article  CAS  Google Scholar 

  43. Cox, N. J., Hayes, M. G., Roe, C. A., Tsuchiya, T. & Bell, G. I. Linkage of calpain 10 to type 2 diabetes: the biological rationale. Diabetes 53, S19–S25 (2004).

    Article  CAS  Google Scholar 

  44. Zhou, Y. P. et al. A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin. Metabolism 52, 528–534 (2003).

    Article  CAS  Google Scholar 

  45. Marshall, C. et al. Evidence that an isoform of calpain-10 is a regulator of exocytosis in pancreatic β-cells. Mol. Endocrinol. 19, 213–224 (2005).

    Article  CAS  Google Scholar 

  46. Asfari, M. et al. Establishment of 2-mercaptoethanol-dependent differentiated insulin-secreting cell lines. Endocrinol. 130, 167–178 (1992).

    Article  CAS  Google Scholar 

  47. Gotoh, M., Maki, T., Kiyoizumi, T., Satomi, S. & Monaco, A. P. An improved method for isolation of mouse pancreatic islets. Transplantation 40, 437–438 (1985).

    Article  CAS  Google Scholar 

  48. Ort, T. et al. The receptor tyrosine phosphatase-like protein ICA512 binds the PDZ domains of β2-syntrophin and nNOS in pancreatic β-cells. Eur. J. Cell Biol. 79, 621–630 (2000).

    Article  CAS  Google Scholar 

  49. Schmidt, D. & Muller, S. Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc. Natl Acad. Sci. USA 99, 2872–2877 (2002).

    Article  CAS  Google Scholar 

  50. Williams C. C. et al. The ERBB4–HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone. J. Cell Biol. 167, 469–478 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to P. De Camilli, M. Matteoli and M. Zerial for critical reading of the manuscript; A. Barthel, R. Grosschedl, R. Janknech, F. White and H. Saitoh for reagents; F. Ehehalt, K. Erdmann and M. Jäger for help in islet isolation; K. Pfriem for excellent assistance; and G. Nikolova and all members of the Solimena lab for advice. This work was supported by funds from the Alexander von Humboldt Foundation, the German Ministry for Education and Research (BMBF), the European Foundation for the Study of Diabetes and the Juvenile Diabetes Research Foundation to M.S., and a MedDrive Grant from the Medical School of Dresden Univsity of Technology to H.M. and M.T.

Author information

Authors and Affiliations

  1. Experimental Diabetology, School of Medicine, Dresden University of Technology, Dresden, 01307, Germany

    Hassan Mziaut, Mirko Trajkovski, Stephan Kersting, Armin Ehninger, Anke Altkrüger & Michele Solimena

  2. Department of Surgery, School of Medicine, Dresden University of Technology, Dresden, 01307, Germany

    Stephan Kersting & Hans-Detlev Saeger

  3. Medical Clinic III, School of Medicine, Dresden University of Technology, Dresden, 01307, Germany

    Michele Solimena

  4. Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, 01307, Germany

    Régis P. Lemaitre & David N. Drechsel

  5. Max Planck Institute for Biochemistry, Martinsried, 82152, Germany

    Darja Schmidt & Stefan Müller

  6. Department of Medicine, Samsung Medical Center, Sungkyunkwan Univ. School of Medicine, Seoul, 135–710, Korea

    Myung-Shik Lee

Authors
  1. Hassan Mziaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mirko Trajkovski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephan Kersting
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Armin Ehninger
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anke Altkrüger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Régis P. Lemaitre
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Darja Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hans-Detlev Saeger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Myung-Shik Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David N. Drechsel
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stefan Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Michele Solimena
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michele Solimena.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures S1, S2, S3 and S4 Original Images 1 and 2 (PDF 345 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mziaut, H., Trajkovski, M., Kersting, S. et al. Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5. Nat Cell Biol 8, 435–445 (2006). https://doi.org/10.1038/ncb1395

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1395

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