title: SOCS2 negatively regulates growth hormone action in vitro and in vivo.
abstract: Mice deficient in SOCS2 display an excessive growth phenotype characterized by a 30-50% increase in mature body size. Here we show that the SOCS2-/- phenotype is dependent upon the presence of endogenous growth hormone (GH) and that treatment with exogenous GH induced excessive growth in mice lacking both endogenous GH and SOCS2. This was reflected in terms of overall body weight, body and bone lengths, and the weight of internal organs and tissues. A heightened response to GH was also measured by examining GH-responsive genes expressed in the liver after exogenous GH administration. To further understand the link between SOCS2 and the GH-signaling cascade, we investigated the nature of these interactions using structure/function and biochemical interaction studies. Analysis of the 3 structural motifs of the SOCS2 molecule revealed that each plays a crucial role in SOCS2 function, with the conserved SOCS-box motif being essential for all inhibitory function. SOCS2 was found to bind 2 phosphorylated tyrosines on the GH receptor, and mutational analysis of these amino acids showed that both were essential for SOCS2 function. Together, the data provide clear evidence that SOCS2 is a negative regulator of GH signaling.
authors.affiliation: Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research (WEHI) and the Cooperative Centre for Cellular Growth Factors, Parkville, Victoria, Australia. greenlaugh@wehi.edu.au
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Greenhalgh
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rico-Bautista
authors.forename: Mattias
authors.initials: M
authors.lastname: Lorentzon
authors.forename: Anne L
authors.initials: AL
authors.lastname: Thaus
authors.forename: Phillip O
authors.initials: PO
authors.lastname: Morgan
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Willson
authors.forename: Panagiota
authors.initials: P
authors.lastname: Zervoudakis
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Ian
authors.initials: I
authors.lastname: Street
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Nicola
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Nash
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Fabri
authors.forename: Gunnar
authors.initials: G
authors.lastname: Norstedt
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.forename: Amilcar
authors.initials: A
authors.lastname: Flores-Morales
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D013006:Growth Hormone / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011986:Receptors, Somatotropin; D012097:Repressor Proteins; C491409:Socs2 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone