Radiosensitization by targeting a novel MAP3K negative regulator STK38

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Serine-threonine kinase 38 (STK38) is a member of the protein kinase A (PKA)/PKG/PKC-like family (AGC). However, little is known about its functions or regulatory mechanisms. Among various environmental stresses, STK38 was specifically activated by X-irradiation or H_2O_2, and the phosphatidylinositol 3-kinase inhibitor wortmannin or AKT inhibitor IV suppressed this activation. STK38 was also activated by a constitutively active AKT1 or by GSK-3beta inhibitor VII. Co-immunoprecipitation analysis revealed that GSK-3 physically interacted with STK38 in cells. Overexpression of GSK-3beta inhibited the oxidative stress-stimulated STK38 activity. We identified GSK-3 as an STK38 kinase. GSK-3beta phosphorylated STK38 on residues S6 and T7 in vitro, largely depending on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively. STK38's oxidative stress-stimulated activity was enhanced by alanine substitution at its priming sites and/or at S6 and T7, but was partially reduced by a phosphomimetic mutation at S6 or T7. Knockdown or overexpression of the phosphomimetic mutant of STK38 enhanced oxidative stress-induced cell death. Taken together, our results indicate that that GSK-3 inhibits STK38 full activation through phosphorylation, and suggest that the activation of STK38 is required for preventing cell death against oxidative stress.