Suppressor of Cytokine Signaling (SOCS) proteins inhibit the GH signal; SOCS2 null mice exhibit giantism (Greenhalgh et al. 2005). Suppressor of Cytokine Signaling (SOCS)1-3, and the realted Cytokine-inducible SH2-containing protein (CIS) all bind tyrosine-phosphorylated GHR; SOCS1 can also binds GHR in the absence of tyrosine phosphorylation (Ram & Waxman 1999, Hansen et al. 1999). SOCS3 binding has been mapped to phosphorylated tyrosines Y338, Y333 (Ram & Waxman 1999), and Y487 (Hansen et al. 1999) in the membrane proximal region of the receptor while SOCS2 and CIS bind to residues Y487 and Y595 (Uyttendaele et al. 2007). SOCS2/3/CIS may compete with STAT5 for GHR binding at these sites but in the case of SOCS3 also appears to act by inhibiting JAK2 directly (Yasukawa et al. 1999).