Serine-Threonine Kinase 38 is regulated by Glycogen Synthase Kinase-3 and modulates oxidative stress-induced cell death

Serine-threonine kinase 38 (STK38) is a member of the protein kinase A (PKA)/PKG/PKC-like family. In the present study, we investigated the regulatory mechanism of STK38 and assessed its role in the cellular stress response. Among various environmental stresses. STK38 was specifically activated by H(2)O(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-3 beta inhibitor VII. The phosphorylation level of GSK-3 beta was correlated with the STK38 activity, in response to various stimuli and in different cell lines. Co-immunoprecipitation analysis revealed that GSK-3 beta physically interacted with STK38 in cells. GSK-3 beta over-expression inhibited the H(2)O(2)-stimulated STK38 activity. GSK-3 beta phosphorylated STK38 on residues S6 and 17 in vitro, depending largely on a PKA-mediated priming phosphorylation of STK38 on residues S10 and S11, respectively. STK38's H(2)O(2)-stimulated activity was enhanced by alanine substitution at its priming sites and/or at S6 and 17, and it was partially reduced by a phosphomimetic mutation at S6 or T7. STK38 knockdown enhanced the H(2)O(2)-induced JNK phosphorylation and cell death. Our results indicate that that GSK-3 beta inhibits STK38's full activation, and suggest that STK38 activation is required to prevent cell death in response to oxidative stress. (C) 2011 Elsevier Inc. All rights reserved.