The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels

Mattias Vesterlund, Fahad Zadjali, Torbjörn Persson, Michael Lund Nielsen, Benedikt M. Kessler, Gunnar Norstedt, Amilcar Flores-Morales

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Growth Hormone is essential for the regulation of growth and the homeostatic control of intermediary metabolism. GH actions are mediated by the Growth Hormone Receptor; a member of the cytokine receptor super family that signals chiefly through the JAK2/STAT5 pathway. Target tissue responsiveness to GH is under regulatory control to avoid excessive and off-target effects upon GHR activation. The suppressor of cytokine signalling 2 (SOCS) is a key regulator of GHR sensitivity. This is clearly shown in mice where the SOCS2 gene has been inactivated, which show 30-40% increase in body length, a phenotype that is dependent on endogenous GH secretion. SOCS2 is a GH-stimulated, STAT5b-regulated gene that acts in a negative feedback loop to downregulate GHR signalling. Since the biochemical basis for these actions is poorly understood, we studied the molecular function of SOCS2. We demonstrated that SOCS2 is part of a multimeric complex with intrinsic ubiquitin ligase activity. Mutational analysis shows that the interaction with Elongin B/C controls SOCS2 protein turnover and affects its molecular activity. Increased GHR levels were observed in livers from SOCS2 -/- mice and in the absence of SOCS2 in in vitro experiments. We showed that SOCS2 regulates cellular GHR levels through direct ubiquitination and in a proteasomally dependent manner. We also confirmed the importance of the SOCS-box for the proper function of SOCS2. Finally, we identified two phosphotyrosine residues in the GHR to be responsible for the interaction with SOCS2, but only Y487 to account for the effects of SOCS2. The demonstration that SOCS2 is an ubiquitin ligase for the GHR unveils the molecular basis for its physiological actions.

Original languageEnglish
Article numbere25358
JournalPLoS One
Volume6
Issue number9
DOIs
Publication statusPublished - Sep 29 2011

Fingerprint

Somatotropin Receptors
Ligases
ubiquitin
Ubiquitin
ligases
cytokines
Cytokines
Phosphotyrosine
Cytokine Receptors
Ubiquitination
mice
Genes
protein metabolism
somatotropin
body length
Growth Hormone
Down-Regulation
genes
secretion
Phenotype

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Vesterlund, M., Zadjali, F., Persson, T., Nielsen, M. L., Kessler, B. M., Norstedt, G., & Flores-Morales, A. (2011). The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels. PLoS One, 6(9), [e25358]. https://doi.org/10.1371/journal.pone.0025358

The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels. / Vesterlund, Mattias; Zadjali, Fahad; Persson, Torbjörn; Nielsen, Michael Lund; Kessler, Benedikt M.; Norstedt, Gunnar; Flores-Morales, Amilcar.

In: PLoS One, Vol. 6, No. 9, e25358, 29.09.2011.

Research output: Contribution to journalArticle

Vesterlund, M, Zadjali, F, Persson, T, Nielsen, ML, Kessler, BM, Norstedt, G & Flores-Morales, A 2011, 'The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels', PLoS One, vol. 6, no. 9, e25358. https://doi.org/10.1371/journal.pone.0025358
Vesterlund M, Zadjali F, Persson T, Nielsen ML, Kessler BM, Norstedt G et al. The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels. PLoS One. 2011 Sep 29;6(9). e25358. https://doi.org/10.1371/journal.pone.0025358
Vesterlund, Mattias ; Zadjali, Fahad ; Persson, Torbjörn ; Nielsen, Michael Lund ; Kessler, Benedikt M. ; Norstedt, Gunnar ; Flores-Morales, Amilcar. / The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels. In: PLoS One. 2011 ; Vol. 6, No. 9.
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