Skip to main content

Thank you for visiting 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.

Gigantism in mice lacking suppressor of cytokine signalling-2


Suppressor of cytokine signalling-2 (SOCS-2) is a member of the suppressor of cytokine signalling family, a group of related proteins implicated in the negative regulation of cytokine action through inhibition of the Janus kinase (JAK) signal transducers and activators of transcription (STAT) signal-transduction pathway1. Here we use mice unable to express SOCS-2 to examine its function in vivo. SOCS-2-/- mice grew significantly larger than their wild-type littermates. Increased body weight became evident after weaning and was associated with significantly increased long bone lengths and the proportionate enlargement of most organs. Characteristics of deregulated growth hormone and insulin-like growth factor-I (IGF-I) signalling, including decreased production of major urinary protein, increased local IGF-I production, and collagen accumulation in the dermis, were observed in SOCS-2-deficient mice, indicating that SOCS-2 may have an essential negative regulatory role in the growth hormone/IGF-I pathway.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Disruption of the SOCS-2 locus by homologous recombination.
Figure 2: Excessive growth of SOCS-2-/- mice.
Figure 3: Pathology in SOCS-2-/- mice.
Figure 4: Deregulated growth hormone signalling in SOCS-2-/- mice.


  1. 1

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

    ADS  CAS  Article  Google Scholar 

  2. 2

    Hilton, D. J. Negative regulators of cytokine signal transduction. Cell. Mol. Life Sci. 55, 1568–1577 (1999).

    CAS  Article  Google Scholar 

  3. 3

    Schoenle, E., Zapf, J., Humbel, R. E. & Froesch, E. R. Insulin-like growth factor I stimulates growth in hypophysectomized rats. Nature 296, 252–253 ( 1982).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Jones, J. I. & Clemmens, D. R. Insulin-like growth factors and their binding proteins: biological actions. Endocrine Rev. 16, 3–34 (1995 ).

    CAS  Google Scholar 

  5. 5

    Shobe, L., An, M. R., Frank, S. J. & Lowe, W. L. Developmental regulation of insulin-like growth factor-I and growth hormone receptor gene expression. Mol. Cell. Endocrinol. 152, 125–136 (1999).

    Article  Google Scholar 

  6. 6

    Mathews, L. S., Enberg, B. & Norstedt, G. Regulation of rat growth hormone receptor gene expression. J. Biol. Chem. 264, 9905– 9910 (1989).

    CAS  PubMed  Google Scholar 

  7. 7

    Kopchick, J. J., Bellush, L. L. & Coschigano, K. T. Transgenic models of growth hormone action. Annu. Rev. Nutrition 19, 437–461 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Daughaday, W. H. in Endocrinology (ed. DeGroot, L. J.) 303– 329 (W. B. Saunders Company, Philidelphia, 1995).

    Google Scholar 

  9. 9

    Quaife, C. J. et al. Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 124, 40–48 ( 1989).

    CAS  Article  Google Scholar 

  10. 10

    Wanke, R. et al. Overgrowth of skin in growth hormone transgenic mice depends on the presence of male gonads. J. Invest. Dermatol. 113, 967–971 (1999).

    CAS  Article  Google Scholar 

  11. 11

    Norstedt, G. & Palmiter, R. Secretory rhythm of growth hormone regulates sexual differentiation of mouse liver. Cell 36, 805–812 (1984).

    CAS  Article  Google Scholar 

  12. 12

    Yakar, S. et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc. Natl Acad. Sci. USA 96, 7324–7329 (1999).

    ADS  CAS  Article  Google Scholar 

  13. 13

    Sjogren, K. et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc. Natl Acad. Sci. USA 96, 7088–7092 (1999).

    ADS  CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    Favre, H., Benhamou, A., Finidori, J., Kelly, P. A. & Edery, M. Dual effects of suppressor of cytokine signaling (SOCS-2) on growth hormone signal transduction. FEBS Lett. 453, 63–66 ( 1999).

    CAS  Article  Google Scholar 

  16. 16

    Tollet-Egnell, P., Flores-Morales, A., Stavreus-Evers, A., Sahlin, L. & Norstedt, G. Growth hormone regulation of SOCS-2, SOCS-3, and CIS messenger ribonucleic acid expression in the rat. Endocrinology 140, 3693–3704 (1999).

    CAS  Article  Google Scholar 

  17. 17

    Davey, H. W., McLachlan, M. J., Wilkins, R. J., Hilton, D. J. & Adams, T. E. STAT5b mediates the growth hormone-induced expression of SOCS-2 and SOCS-3 mRNA in the liver. Mol. Cell. Endocrinol. 158, 111–116 ( 1999).

    CAS  Article  Google Scholar 

  18. 18

    Ram, P. A. & Waxman, D. J. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J. Biol. Chem. 274, 35553–35561 (1999).

    CAS  Article  Google Scholar 

  19. 19

    Hansen, J. A., Lindberg, K., Hilton, D. J., Nielsen, J. H. & Billestrup, N. Mechanism of inhibition of growth hormone receptor signaling by suppressor of cytokine signaling proteins. Mol. Endocrinol. 13, 1832–1843 (1999).

    CAS  Article  Google Scholar 

  20. 20

    Matsumoto, A. et al. Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice. Mol. Cell. Biol. 19, 6396–6407 (1999).

    CAS  Article  Google Scholar 

  21. 21

    Dey, B. R., Spence, S. L., Nissley, P. & Furlanetto, R. W. Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor-I receptor. J. Biol. Chem. 273, 24095–24101 (1998).

    CAS  Article  Google Scholar 

  22. 22

    Lopaczynski, W. Differential regulation of signaling pathways for insulin and insulin- like growth factor I. Acta Biochim. Pol. 46, 51–60 (1999).

    CAS  PubMed  Google Scholar 

  23. 23

    Starr, R. et al. Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signalling-1. Proc. Natl Acad. Sci. USA 95, 14395–14399 ( 1998).

    ADS  CAS  Article  Google Scholar 

  24. 24

    Alexander, W. S., Metcalf, D. & Dunn, A. R. Point mutations within a dimer interface homolgy domain of c-mpl induce constitutive receptor activity and tumorigenesis. EMBO J. 14, 5569–5578 ( 1995).

    CAS  Article  Google Scholar 

  25. 25

    Alexander, W. S., Roberts, A. W., Nicola, N. A., Li, R. & Metcalf, D. Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic receptor c-Mpl. Blood 87 , 2162–2170 (1996).

    CAS  PubMed  Google Scholar 

Download references


We thank N. Sprigg, J. Mighall, S. Mifsud and L. DiRago for technical assistance; K. Hanzinikolas for animal care; S. Mihajlovic for histology; and F. Koentgen, L. Barnett, J. DeWinter and M. Swift of the Walter and Eliza Hall Institute Genetically Modified Mouse Facility and T. Adams for discussions and critical assessment of the manuscript. This work was supported by the National Health and Medical Research Council, Canberra, the Anti-Cancer Council of Victoria, an Australian Government Cooperative Research Centres Program Grant, the National Institutes of Health, Bethesda, the J. D. and L. Harris Trust and AMRAD Operations Pty Ltd, Melbourne.

Author information



Corresponding author

Correspondence to Warren S. Alexander.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Metcalf, D., Greenhalgh, C., Viney, E. et al. Gigantism in mice lacking suppressor of cytokine signalling-2. Nature 405, 1069–1073 (2000).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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