title: The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels.
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.
authors: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors: Mattias
authors: M
authors: Vesterlund
authors: Fahad
authors: F
authors: Zadjali
authors: Torbjörn
authors: T
authors: Persson
authors: Michael Lund
authors: ML
authors: Nielsen
authors: Benedikt M
authors: BM
authors: Kessler
authors: Gunnar
authors: G
authors: Norstedt
authors: Amilcar
authors: A
authors: Flores-Morales
mesh_terms: D000818:Animals; D015536:Down-Regulation; D000075065:Elongin; D013006:Growth Hormone / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D011986:Receptors, Somatotropin / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination; D018909:src Homology Domains
chemical_list: C000616396:ELOB protein, human; C000616401:Elob protein, mouse; D000075065:Elongin; D011986:Receptors, Somatotropin; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014443:Tyrosine; D013006:Growth Hormone; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex