Abstract
Serine-threonine kinase 38 (STK38) is a member of the AGC (protein kinase A (PKA)/PKG/PKC-like) family. However, little is known about its functions or regulatory mechanisms. Here, we report that STK38 is a target of glycogen synthase kinase-3 (GSK-3). STK38 was specifically activated by H2O2 among several environmental stresses, which was suppressed by the PI-3K inhibitor wortmannin. STK38 was also activated by a constitutively active AKT1, a GSK-3b inhibitor, or the knockdown of GSK-3 a/b. GSK-3b phosphorylated STK38 on serine 6 (S6) and threonine 7 (T7) in vitro, which required a priming phosphorylation of STK38 on serine 10 (S10) and serine 11 (S11), respectively. Expression of GSK-3b inhibited the H2O2-stimulated STK38 activity. Treatment with H2O2 rapidly diminished the GSK-3b-mediated STK38 phosphorylation. Substituting alanine for S6, T7, and/or for the priming phosphorylation sites on STK38 enhanced its H2O2-stimulated activity, but a phosphomimetic mutation at S6 or T7 reduced it. Moreover, knocking down STK38 enhanced H2O2-induced JNK phosphorylation and cell death. Taken together, our results indicate that GSK-3 negatively regulates the activation of STK38 by phosphorylation and that STK38 promotes cell survival by modulating JNK signaling, suggesting a possible cell survival-regulating pathway branching downstream of PI-3K/AKT.
