Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38γ

The human protein tyrosine phosphatase non-receptor type 4 (PTPN4) prevents cell death induction in neuroblastoma and glioblastoma cell lines in a PDZ center dot PDZ binding motifs-dependent manner, but the cellular partners of PTPN4 involved in cell protection are unknown. Here, we described the mitogen-activated protein kinase p38 gamma as a cellular partner of PTPN4. The main contribution to the p38 gamma center dot PTPN4 complex formation is the tight interaction between the C terminus of p38 gamma and the PDZ domain of PTPN4. We solved the crystal structure of the PDZ domain of PTPN4 bound to the p38 gamma C terminus. We identified the molecular basis of recognition of the C-terminal sequence of p38 gamma that displays the highest affinity among all endogenous partners of PTPN4. We showed that the p38 gamma C terminus is also an efficient inducer of cell death after its intracellular delivery. In addition to recruiting the kinase, the binding of the C-terminal sequence of p38 gamma to PTPN4 abolishes the catalytic auto-inhibition of PTPN4 and thus activates the phosphatase, which can efficiently dephosphorylate the activation loop of p38 gamma. We presume that the p38 gamma center dot PTPN4 interaction promotes cellular signaling, preventing cell death induction.