SOCS1 can bind JAK2 and inhibit JAK kinase activity (Yasukawa et al. 1999). SOCS3 also inhibits JAK2 kinase activity (Sasaki et al. 1999) while all of SOCS1 -3 and CIS inhibit GHR signaling (Ram & Waxman 1999, Nicholson et al. 2000). This is not thought to be simply the outcome of binding competition between SOCS and STAT5, but a direct action of SOCS on JAK2 (Ram & Waxman 1999). Although SOCS are known to be ubiquitin ligases (Kamura et al. 2004), ubiquitin ligase activity on JAK2 or GHR has not been demonstrated and a role for SOCS in the ubiquitination of these proteins has been questioned (Flores-Morales et al. 2006). An alternative model suggested by the observation that SOCS3 strongly inhibits JAK2 only in the presence of GHR proposes that SOCS serve as an inhibitory 'bridge' by binding simultaneously to GHR and JAK2 (Ram & Waxman 1999).