Protein kinase A phosphorylates and regulates dimerization of 14-3-3ζ

Recognition of phosphorylated serine/threonine-containing motifs by 14-3-3 depends on the dimerization of 14-3-3. However, the molecular cues that control 14-3-3 dimerization are not well understood. In order to identify proteins that control 14-3-3 dimerization, we analyzed proteins that have effects on 14-3-3 dimerization and report that protein kinase A (PKA) phosphorylates 14-3-3 at a specific residue (Ser58). Phosphorylation by PKA leads to modulation of 14-3-3 zeta dimerization and affect its interaction with partner proteins. Substitution of Ser58 to Ala completely abolished phosphorylation of 14-3-3 zeta by PKA. A phospho-mimic mutant of 14-3-3;, Ser58 to Glu substitution, failed to form homodimers, showed reduced interaction with 14-3-3 zeta and p53, and could not enhance transcriptional activity of p53. Moreover, activation of PKA decreases and inhibition of PKA increases the dimerization of 14-3-3 zeta and the functional interaction of 14-3-3 zeta; with p53. Therefore, our results suggest that PKA is a new member of protein kinases that can phosphorylate and impair the function of 14-3-3. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.