PTPN3 is a protein phosphatase that dephosphorylates MAPK12, also known as p38 gamma. Phosphorylation of the p38 family of MAPK is associated with suppression of RAS signaling, and consistent with this, binding and dephosphorylation of MAPK12 by PTPN3 promotes RAS-induced transformation (Tang et al, 2005; Hou et al, 2010; Chen et al, 2014).
Dephosphorylation is promoted by a direct binding between phosphorylated MAPK12 and PTPN3, mediated by an interaction between the PTPN3 PDZ domain and the isoform-specific ETPL domain of MAPK12. Binding of PTPN3 and phosphorylated MAPK12 relieves an autoinhibitory conformation of the phosphatase and promotes MAPK12 dephosphorylation (Hou et al, 2010; Chen et al, 2014). How dephosphorylated MAPK12 promotes RAS signaling remains to be elucidated.