Molecular Basis of the Interaction of the Human Protein Tyrosine Phosphatase Non-receptor Type 4 (PTPN4) with the Mitogen-activated Protein Kinase p38?.

ABSTRACT: The human protein tyrosine phosphatase non-receptor type 4 (PTPN4) prevents cell death induction in neuroblastoma and glioblastoma cell lines in a PDZ·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? as a cellular partner of PTPN4. The main contribution to the p38?·PTPN4 complex formation is the tight interaction between the C terminus of p38? and the PDZ domain of PTPN4. We solved the crystal structure of the PDZ domain of PTPN4 bound to the p38? C terminus. We identified the molecular basis of recognition of the C-terminal sequence of p38? that displays the highest affinity among all endogenous partners of PTPN4. We showed that the p38? 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? to PTPN4 abolishes the catalytic autoinhibition of PTPN4 and thus activates the phosphatase, which can efficiently dephosphorylate the activation loop of p38?. We presume that the p38?·PTPN4 interaction promotes cellular signaling, preventing cell death induction.

SUBMITTER: Maisonneuve P 

PROVIDER: S-EPMC4974383 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature