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.

  • Letter
  • Published:

Phospholipase Cγ1 negatively regulates growth hormone signalling by forming a ternary complex with Jak2 and protein tyrosine phosphatase-1B

Nature Cell Biology volume 8, pages 1389–1397 (2006)Cite this article

Abstract

Growth hormone binds to its membrane receptor (GHR), whereby it regulates many cellular functions, including proliferation, differentiation and chemotaxis. However, although the activation of growth hormone-mediated signalling is well understood, the precise mechanism responsible for its regulation has not been elucidated. Here, we demonstrate that phospholipase Cγ1 (PLCγ1) modulates the action of growth hormone-mediated signalling by interacting with tyrosine kinase Jak2 (janus kinase 2) in a growth hormone-dependent manner. In the absence of PLCγ1 (PLCγ1−/−), growth hormone-induced JAK2 and STAT5 phosphorylation significantly increased in mouse embryonic fibroblasts (MEFs). Furthermore, the re-expression of PLCγ1 reduced growth hormone-induced Jak2 activation. Growth hormone-induced Jak2 phosphorylation was enhanced by siRNA-specific knockdown of PLCγ1. Interestingly, PLCγ1 physically linked Jak2 and protein tyrosine phosphatase-1B (PTP-1B) by binding to both using different domains, and this process was implicated in the modulation of cytokine signalling through Jak2. In addition, in PLCγ1−/− MEFs, growth hormone-dependent c-Fos activation was upregulated and growth hormone-induced proliferation was potentiated. These results suggest that PLCγ1 has a key function in the regulation of growth hormone-mediated signalling by negatively regulating Jak2 activation.

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: PLCγ1 was activated by Jak2 through their interaction.
Figure 2: PLCγ1 specifically attenuated growth hormone-induced Jak2 and STAT5 activation.
Figure 3: PLCγ1 physically links Jak2 and PTP-1B.
Figure 4: PLCγ1–PTP-1B complex attenuated growth hormone-induced STAT5 activation.
Figure 5: PLCγ1 attenuated growth hormone-mediated transcriptional activity and cellular proliferation.

Similar content being viewed by others

References

  1. Lupu, F., Terwilliger, J. D., Lee, K., Segre, G. V. & Efstratiadis, A. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev. Biol. 229, 141–162 (2001).

    Article  CAS  Google Scholar 

  2. Argetsinger, L. S. et al. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 74, 237–244 (1993).

    Article  CAS  Google Scholar 

  3. Herrington, J., & Carter-Su, C. Signaling pathways activated by the growth hormone receptor. Trends Endocrinol. Metab. 12, 252–257 (2001).

    Article  CAS  Google Scholar 

  4. Herrington, J., Smit, L. S., Schwartz, J. & Carter-Su, C. The role of STAT proteins in growth hormone signaling. Oncogene 19, 2585–2597 (2000).

    Article  CAS  Google Scholar 

  5. Fain, J. N. et al. Regulation of phosphoinositide-specific phospholipase C. Biochim. Biophys. Acta. 1053, 81–88 (1990).

    Article  CAS  Google Scholar 

  6. Rhee, S. G. & Bae, Y. S. Regulation of phosphoinositide-specific phospholipase C isozymes. J. Biol. Chem. 272, 15045–15048 (1997).

    Article  CAS  Google Scholar 

  7. Patterson, R. L. et al. Phospholipase C-γ is required for agonist-induced Ca2+ entry. Cell 111, 529–541 (2002).

    Article  CAS  Google Scholar 

  8. Ye, K. et al. Phospholipase C γ 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE. Nature 415, 541–544 (2002).

    Article  CAS  Google Scholar 

  9. Choi, J. H. et al. Phospholipase C-γ1 is a guanine nucleotide exchange factor for dynamin-1 and enhances dynamin-1-dependent epidermal growth factor receptor endocytosis. J. Cell Sci. 117, 3785–3795 (2004).

    Article  CAS  Google Scholar 

  10. Rogers, S. A. & Hammerman, M. R. Growth hormone activates phospholipase C in proximal tubular basolateral membranes from canine kidney. Proc. Natl Acad. Sci. USA 86, 6363–6366 (1989).

    Article  CAS  Google Scholar 

  11. Doglio, A., Dani, C., Grimaldi, P. & Ailhaud, G. Growth hormone stimulates c-fos gene expression by means of protein kinase C without increasing inositol lipid turnover. Proc. Natl Acad. Sci. USA. 86, 1148–1152 (1989).

    Article  CAS  Google Scholar 

  12. Argetsinger, L. S. & Carter-Su, C. Mechanism of signaling by growth hormone receptor. Physiol. Rev. 76, 1089–1107 (1996).

    Article  CAS  Google Scholar 

  13. Sjoholm, A. et al. Rapid Ca2+ influx and diacylglycerol synthesis in growth hormone-mediated islet β-cell mitogenesis. J. Biol. Chem. 275, 21033–21040 (2000).

    Article  CAS  Google Scholar 

  14. Irvin, B. J., Williams, B. L., Nilson, A. E., Maynor, H. O. & Abraham, R. T. Pleiotropic contributions of phospholipase C-γ1 (PLC-γ1) to T-cell antigen receptor-mediated signaling: reconstitution studies of a PLC-γ1-deficient Jurkat T-cell line. Mol. Cell. Biol. 20, 9149–9161 (2000).

    Article  CAS  Google Scholar 

  15. Ji, Q. S. et al. Essential role of the tyrosine kinase substrate phospholipase C-γ1 in mammalian growth and development. Proc. Natl Acad. Sci. USA 94, 2999–3003 (1997).

    Article  CAS  Google Scholar 

  16. Strous, G. J., van, Kerkhof. P., Govers, R., Ciechanover, A. & Schwartz, A. L. The ubiquitin conjugation system is required for ligand-induced endocytosis and degradation of the growth hormone receptor. EMBO J. 15, 3806–3812 (1996).

    Article  CAS  Google Scholar 

  17. Narazaki, M. et al. Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130. Proc. Nat. Acad. Sci. USA 91, 2285–2289 (1994).

    Article  CAS  Google Scholar 

  18. Myers, M. P. et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J. Biol. Chem. 276, 47771–47774 (2001).

    Article  CAS  Google Scholar 

  19. 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 

  20. Watanabe, S., Itoh, T. & Arai, K. JAK2 is essential for activation of c-fos and c-myc promoters and cell proliferation through the human granulocyte-macrophage colony-stimulating factor receptor in BA/F3 cells. J. Biol. Chem. 271, 12681–12686 (1996).

    Article  CAS  Google Scholar 

  21. Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J. & Efstratiadis, A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59–72 (1993).

    CAS  PubMed  Google Scholar 

  22. Heinrich, P. C. et al. Principles of IL-6-type cytokine signaling and its regulation. Biochem. J. 374, 1–20 (2003).

    Article  CAS  Google Scholar 

  23. Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).

    Article  CAS  Google Scholar 

  24. Klaman, L. D. et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol. Cell. Biol. 20, 5479–5489 (2000).

    Article  CAS  Google Scholar 

  25. Kofoed, E. M. et al. Growth hormone insensitivity associated with a STAT5b mutation. N. Engl. J. Med. 349, 1139–1147 (2003).

    Article  CAS  Google Scholar 

  26. Cressman, D. E. et al. Liver failure and defective hepatocyte regeneration in interleukin-6-defcient mice. Science 274, 1379–1383 (1996).

    Article  CAS  Google Scholar 

  27. Waters, M. J., Hoang, H. N., Fairlie, D. P., Pelekanos, R. A. & Brown, R. J. New insights into growth hormone action. J. Mol. Endocrinol. 36, 1–7 (2006).

    Article  CAS  Google Scholar 

  28. Sangwan, Y. et al. Protein-tyrosine phosphatase 1B deficiency protects against Fas-induced hepatic failure. J. Biol. Chem. 281, 221–228 (2006).

    Article  CAS  Google Scholar 

  29. Liu, F. & Chernoff, J. Protein tyrosine phosphatase 1B interacts with and is tyrosine phosphorylated by the epidermal growth factor receptor. Biochem J. 327, 139–145 (1997).

    Article  CAS  Google Scholar 

  30. Peng, B. et al. CPAP is a novel stat5-interacting cofactor that augments stat5-mediated transcriptional activity. Mol. Endocrinol. 16, 2019–2033 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National R&D Program for Fusion Strategy of Advanced Technologies of Ministry of Commerce, Industry and Energy (MOCIE). This work was supported by the National Research Laboratory of the Korea Science and Engineering Foundation (grant M10600000281-06J0000-28110) and Brain Korea21 Program of the Ministry of Education of Korea.

Author information

Authors and Affiliations

  1. National Research Laboratory of Signaling Network,Department of Life Science, Pohang University of Science and Technology, Pohang, 790-784, Kyungbuk, Republic of Korea

    Jang Hyun Choi, Hyeon Soo Kim, Sun-Hee Kim, Yong Ryoul Yang, Sung Ho Ryu & Pann-Ghill Suh

  2. Divisions of Molecular Life Sciences, Center for Cell Signalling Research, Ewha Womans University, Seoul, 120-750, Republic of Korea

    Yun Soo Bae

  3. Department of Life Science, College of Natural Science, Daejin University, Kyeonggido, 487-711, Republic of Korea

    Jong-Soo Chang

  4. Divisions of Nephrology, University of Maryland, Baltimore, 21201, MD, USA

    H. Moo Kwon

Authors
  1. Jang Hyun Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyeon Soo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sun-Hee Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong Ryoul Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yun Soo Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jong-Soo Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. Moo Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sung Ho Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pann-Ghill Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pann-Ghill Suh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figures S1, S2, S3 and Supplementary methods (PDF 400 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Choi, J., Kim, H., Kim, SH. et al. Phospholipase Cγ1 negatively regulates growth hormone signalling by forming a ternary complex with Jak2 and protein tyrosine phosphatase-1B. Nat Cell Biol 8, 1389–1397 (2006). https://doi.org/10.1038/ncb1509

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1509

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