Suppressor of cytokine signaling protein 3 (SOCS3) binds to the same gp130 phosphotyrosine (Tyr-759) as SHP2 (Schmitz et al. 2000) though they appear to suppress IL-6 signaling by independent mechanisms (Lehmann et al. 2003).
Members of the SOCS family (CIS and SOCS1-7) have an N-terminal SH2 domain preceded by an extended SH2 domain (ESS) and kinase inhibitory region (KIR) (Hilton et al. 1998). The related SOCS1 associates with JAKs via its KIR and SH2 domains (Narazaki et al. 1998, Yasukawa et al. 1999) leading to inhibition of JAK signaling and kinase activity. SOCS3 was unable to inhibit JAK kinase activity in vitro, suggesting that SOCS1 and SOCS3 inhibit signaling in different ways (Nicholson et al. 1999), but it is possible that SOCS3's inhibitory actions require binding to both activated receptor gp130 Tyr-759 and the associated JAK for maximal inhibition (Greenhalgh & Hilton 2001). Socs3 deficiency results in prolonged STAT1/3 activation after IL-6 but not interferon-gamma stimulation suggesting that SOCS3 has a role in preventing IFN-gamma-like responses in cells stimulated by IL-6 (Croker et al. 2003).