SOCS3, induced by activated STAT3, binds autophosphorylated PTK6 (BRK) and inhibits its catalytic activity and phosphorylation of STAT3, thus creating a negative feedback loop (Liu et al. 2006). The SH2 domain of SOCS3 binds to the kinase domain of autophosphorylated PTK6. Autophosphorylation of PTK6 on tyrosine residue Y251 (not shown) may be necessary for SOCS3 binding. Inhibition of the kinase activity of PTK6 requires the kinase inhibitory region (KIR) of SOCS3. SOCS3 may also modestly reduce PTK6 protein levels by recruiting ubiquitin ligases to PTK6, which requires the SOCS box of SOCS3 (Gao et al. 2012).