title: Functional cross-modulation between SOCS proteins can stimulate cytokine signaling.
abstract: SOCS (suppressors of cytokine signaling) proteins are negative regulators of cytokine signaling that function primarily at the receptor level. Remarkably, in vitro and in vivo observations revealed both inhibitory and stimulatory effects of SOCS2 on growth hormone signaling, suggesting an additional regulatory level. In this study, we examined the possibility of direct cross-modulation between SOCS proteins and found that SOCS2 could interfere with the inhibitory actions of other SOCS proteins in growth hormone, interferon, and leptin signaling. This SOCS2 effect was SOCS box-dependent, required recruitment of the elongin BC complex, and coincided with degradation of target SOCS proteins. Detailed mammalian protein-protein interaction trap (MAPPIT) analysis indicated that SOCS2 can interact with all members of the SOCS family. SOCS2 may thus function as a molecular bridge between a ubiquitin-protein isopeptide ligase complex and SOCS proteins, targeting them for proteasomal turnover. We furthermore extended these observations to SOCS6 and SOCS7. Our findings point to a unique regulatory role for SOCS2, SOCS6, and SOCS7 within the SOCS family and provide an explanation for the unexpected phenotypes observed in SOCS2 and SOCS6 transgenic mice.
authors.affiliation: Flanders Interuniversity Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Piessevaux
authors.forename: Delphine
authors.initials: D
authors.lastname: Lavens
authors.forename: Tony
authors.initials: T
authors.lastname: Montoye
authors.forename: Joris
authors.initials: J
authors.lastname: Wauman
authors.forename: Dominiek
authors.initials: D
authors.lastname: Catteeuw
authors.forename: Joël
authors.initials: J
authors.lastname: Vandekerckhove
authors.forename: Denise
authors.initials: D
authors.lastname: Belsham
authors.forename: Frank
authors.initials: F
authors.lastname: Peelman
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism*; D000075065:Elongin; D006801:Humans; D051379:Mice; D011485:Protein Binding; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016207:Cytokines; D000075065:Elongin; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors