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The mitogen-activated protein kinases (MAPKs) are key signaling enzymes that play critical roles in cellular signal transduction pathways such as cell survival, proliferation, differentiation, and apoptosis. The three major groups of MAPK that are expressed in mammals are p38, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK). Signaling by MAPKs is processed following their phosphorylation at conserved threonine and tyrosine residues within the activation loop of MAPKs mediated by their upstream kinases in activation. Protein tyrosine phosphatases (PTPs) are responsible for regulation of MAPK activity through dephosphorylation of phospho-threonine and phospho-tyrosine residues on MAPKs. The human genome encodes 107 PTPs. PTPs can be classified into four groups based on amino-acid sequences of catalytic domains. They are class I Cys-based PTPs, class II Cys-based PTPs, class III Cys-based PTPs, and Asp-based PTPs. Especially, protein tyrosine phosphatase non-receptor type 2 (PTPN2) that is also known as T cell protein tyrosine phosphatase (TC-PTP) belongs to class I Cys-based PTPs as the intracellular, non-receptor PTPs (NRPTPs) with a high degree of sequence and structural homology within the catalytic domain. PTPN2 has been reported to modulate cytokine receptor signaling, including IFN-γ signaling. PTPN2 dephosphorylates and inactivates Src tyrosine kinases to suppress downstream signaling through ERK and production of interleukin 6. In a way to study biological functions of PTPN2, we performed the regulatory mechanism of PTPN2 activity using a specific chemical compound, ethyl-3,4-dephostatin. Ethyl-3,4-dephostatin (Fig. 1) was originally identified as a potent PTP-1B and src homology-2-containing protein tyrosine phosphatase-1 (SHP-1) inhibitor and showed inhibitory effect on several PTPs in vitro. Recently, dual-specificity phosphatase 22 (DUSP22) was identified as an additional target of ethyl-3,4-dephostatin. To investigate whether ethyl-3,4-dephostatin was able to inhibit PTPN2 activity, we treated various concentrations of ethyl-3,4-dephostatin on purified active PTPN2. PTPN2 activity was decreased by ethyl-3,4-dephostatin in a dosedependent manner. The half maximal inhibitory concentration (IC50) of PTPN2 was found to be about 6.5 ± 0.54 μM by using the curve fitting program PRISM 3.0 (Fig. 2(a)). In addition, the Lineweaver-Burk plot shows that the Ki was 8.6 μM (Fig. 2(b)). This result indicates that ethyl-3,4dephostatin acts as a competitive inhibitor of PTPN2, suggesting that ethyl-3,4-dephostatin suppresses the activity of PTPN2 through binding to the catalytic site. We further examined whether ethyl-3,4-dephostatin influences PTPN2-mediated ERK inhibition in vivo. Since PTPN2 inactivates Src tyrosine kinases that are located upstream of ERK signaling, we overexpressed PTPN2 in HEK 293 cells and detected phosphorylation levels of endogenous ERK after treatment with ethyl-3,4-dephostatin. HEK 293 cells were transfected with FLAG-PTPN2 expression plasmid and

Ethyl-3,4-dephostatin Inhibits PTPN2 and Induces ERK Activation