title: Suppressor of cytokine signaling (SOCS)-5 is a potential negative regulator of epidermal growth factor signaling.
abstract: The suppressors of cytokine signaling (SOCS) proteins are a family of SH2 domain-containing intracellular inhibitors of cytokine signal transduction that act by several different mechanisms. Recent evidence suggests that the action of the SOCS proteins may extend beyond the cytokine receptors to signaling initiated by members of the tyrosine kinase receptor family. In this study, the ability of SOCS-5 to negatively regulate signaling cascades downstream of the epidermal growth factor receptor (EGF-R) has been examined by using an EGF-responsive cell line engineered to constitutively express the EGF-R and SOCS-5 or SOCS-5 mutants. SOCS-5 associated with the EGF-R complex in an EGF-independent manner, and the mitogenic response to EGF of all SOCS-5-expressing cell lines was dramatically inhibited when compared with control cell lines. Furthermore, this effect was abrogated after deletion of the SOCS-5 SOCS box. This result suggests that the inhibition of signaling occurs through enhanced proteasomal degradation of the EGF-R through SOCS box recruitment of E3 ubiquitin ligase activity.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Cooperative Research Centre for Cellular Growth Factors, Parkville, Victoria 3052, Australia. snicholson@wehi.edu.au
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Naomi S
authors.initials: NS
authors.lastname: Sprigg
authors.forename: Ruth
authors.initials: R
authors.lastname: Columbus
authors.forename: Francesca
authors.initials: F
authors.lastname: Walker
authors.forename: Anabel
authors.initials: A
authors.lastname: Silva
authors.forename: Dale
authors.initials: D
authors.lastname: Cary
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Willson
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Nicola
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D016296:Mutagenesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D011506:Proteins; D011994:Recombinant Proteins; C485811:Socs5 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins; D004815:Epidermal Growth Factor; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors