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:

Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras

Nature Cell Biology volume 3, pages 460–465 (2001)Cite this article

Abstract

Suppressors of cytokine signalling (SOCS, also known as CIS and SSI) are encoded by immediate early genes that act in a feedback loop to inhibit cytokine responses and activation of 'signal transducer and activator of transcription' (STAT). Here we show that SOCS-3 is strongly tyrosine-phosphorylated in response to many growth factors, including interleukin-2 (IL-2), erythropoietin (EPO), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). The principal phosphorylation sites on SOCS-3 are residues 204 and 221 at the carboxy terminus, and upon phosphorylation tyrosine 221 interacts with the Ras inhibitor p120 RasGAP. After IL-2 stimulation, phosphorylated SOCS-3 strongly inhibits STAT5 activation but, by binding to RasGAP, maintains activation of extracellular-signal-regulated kinase (ERK). A tyrosine mutant of SOCS-3 still blocks STAT phosphorylation, but also strongly inhibits IL-2-dependent activation of ERK and cell proliferation. Moreover, it also inhibits EPO- and PDGF-induced proliferation and ERK activation. Therefore, although SOCS proteins inhibit growth-factor responses, tyrosine phosphorylation of SOCS-3 can ensure cell survival and proliferation through the Ras pathway.

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: SOCS-3 is phosphorylated at tyrosines 204 and 221.
Figure 2: Tyrosine 221 of SOCS-3 interacts with p120 RasGAP.
Figure 3: Tyrosine-phosphorylated SOCS-3 associates with p120 RasGAP.
Figure 4: Expression of SOCS-3 inhibits STAT5 but not ERK activation.
Figure 5: SOCS-3(Y204,221F) blocks growth-factor-induced cell proliferation.

Similar content being viewed by others

References

  1. O'Shea, J. J., Notrangelo, L. D., Johnston, J. A., Leonard, W. J. & Candotti, F. Advances in the understanding of cytokine signal transduction: the role of JAKs and STATs in immunoregulation and the pathogenesis of immunodeficiency. J. Clin. Immunol. 17, 431–447 (1997).

    Article  CAS  Google Scholar 

  2. Ihle, J. N. & Kerr, I. M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 11, 69–74 (1995).

    Article  CAS  Google Scholar 

  3. Endo, T. A. et al. A new protein containing an SH2 domain that inhibits JAKkinases. Nature 387, 921–924 (1997).

    Article  CAS  Google Scholar 

  4. Hilton, D. J. et al. Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc. Natl Acad. Sci. USA 95, 114–119 (1998).

    Article  CAS  Google Scholar 

  5. Starr, R. et al. A family of cytokine-inducible inhibitors of signalling. Nature 387, 917–921 (1997).

    Article  CAS  Google Scholar 

  6. Naka, T. et al. Structure and function of a new STAT-induced STAT inhibitor. Nature 387, 924–929 (1997).

    Article  CAS  Google Scholar 

  7. Nicholson, S. E. et al. Mutational analysis of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J. 18, 375–385 (1999).

    Article  CAS  Google Scholar 

  8. Yasukawa, H. et al. The JAK-binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J. 18, 1309–1320 (1999).

    Article  CAS  Google Scholar 

  9. Cohney, S. J. et al. SOCS-3 is tyrosine phosphorylated in response to interleukin-2 and suppresses STAT5 phosphorylation and lymphocyte proliferation. Mol. Cell. Biol. 19, 4980–4988 (1999).

    Article  CAS  Google Scholar 

  10. Adams, T. E. et al. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling. J. Biol. Chem. 273, 1285–1287 (1998).

    Article  CAS  Google Scholar 

  11. Bjorbaek, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E. & Flier, J. S. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell 1, 619–625 (1998).

    Article  CAS  Google Scholar 

  12. Marine, J. C. et al. SOCS-3 is essential in the regulation of fetal liver erythropoiesis. Cell 98, 617–627 (1999).

    Article  CAS  Google Scholar 

  13. Trahey, M. & McCormick, F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238, 542–545 (1987).

    Article  CAS  Google Scholar 

  14. Kashige, N., Carpino, N. & Kobayashi, R. Tyrosine phosphorylation of p62dok by p210 bcr-abl inhibits RasGAP activity. Proc. Natl Acad. Sci. USA 97, 2093–2098 (2000).

    Article  CAS  Google Scholar 

  15. Nelms, K., Snow, A. L., Hu-Li, J. & Paul, W. E. FRIP, a hematopoietic cell-specific rasGAP-interacting protein phosphorylated in response to cytokine stimulation. Immunity 9, 13–24 (1998).

    Article  CAS  Google Scholar 

  16. Songyang, Z. et al. SH2 domains recognize specific phosphopeptide sequences. Cell 72, 767–778 (1993).

    Article  CAS  Google Scholar 

  17. Nelson, B. H., Lord, J. D. & Greenberg, P. D. Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation. Nature 369, 333–336 (1994).

    Article  CAS  Google Scholar 

  18. Friedmann, M. C., Migone, T. S., Russell, S. M. & Leonard, W. J. Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation. Proc. Natl Acad. Sci. USA 93, 2077–2082 (1996).

    Article  CAS  Google Scholar 

  19. Suzuki, R. et al. CIS3 and JAB have different regulatory roles in interleukin-6 mediated differentiation and STAT3 activation in M1 leukemia cells. Oncogene 17, 2271–2278 (1998).

    Article  CAS  Google Scholar 

  20. Sasaki, A. et al. Cytokine-inducible SH2 protein-3 (CIS3/SOCS-3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain. Genes Cells 4, 339–351 (1999).

    Article  CAS  Google Scholar 

  21. De Sepulveda, P. et al. Socs1 binds to multiple signalling proteins and suppresses Steel factor- dependent proliferation. EMBO J. 18, 904–915 (1999).

    Article  CAS  Google Scholar 

  22. Emanuelli, B., Peraldi, P., Filloux, C., Hilton, D. J. & Van Obberghen, E. SOCS-3 is an insulin-induced negative regulator of insulin signalling. J. Biol. Chem. 275, 15985–15991 (2000).

    Article  CAS  Google Scholar 

  23. Woods, D. et al. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol. Cell. Biol. 17, 5598–5611 (1997).

    Article  CAS  Google Scholar 

  24. Mui et al. Suppression of interleukin-3-induced gene expression by a C-terminal truncated STAT5: role of STAT5 in proliferation. EMBO J. 5, 2425–2433 (1996)

    Article  Google Scholar 

Download references

Acknowledgements

We thank B. Amati, D. McVicar, R. Herbst and L. Hibbert for discussions. The DNAX Research Institute is supported by Schering Plough, Kenilworth, New Jersey.

Author information

Author notes

  1. James A. Johnston

    Present address: Department of Immunology, Whitla Medical Building, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK

Authors and Affiliations

  1. DNAX Research Institute, 901 California Avenue, Palo Alto, 94304, California, USA

    Nicholas A. Cacalano & David Sanden

Authors
  1. Nicholas A. Cacalano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Sanden
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James A. Johnston
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James A. Johnston.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cacalano, N., Sanden, D. & Johnston, J. Tyrosine-phosphorylated SOCS-3 inhibits STAT activation but binds to p120 RasGAP and activates Ras. Nat Cell Biol 3, 460–465 (2001). https://doi.org/10.1038/35074525

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35074525

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