Protein kinase A phosphorylates and regulates dimerization of 14-3-3 epsilon.
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 14-3-3zeta at a specific residue (Ser58). Phosphorylation by PKA leads to modulation of 14-3-3zeta dimerization and affect its interaction with partner proteins. Substitution of Ser58 to Ala completely abolished phosphorylation of 14-3-3zeta by PKA. A phospho-mimic mutant of 14-3-3zeta, Ser58 to Glu substitution, failed to form homodimers, showed reduced interaction with 14-3-3epsilon and p53, and could not enhance transcriptional activity of p53. Moreover, activation of PKA decreases and inhibition of PKA increases the dimerization of 14-3-3zeta and the functional interaction of 14-3-3zeta 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.
Gu
Young-Mi
YM
College of Pharmacy, Chonnam National University, Yongbong-dong 300, Buk-Gu, Gwangju 500757, Republic of Korea.
Jin
Yun-Hye
YH
Choi
Joong-Kook
JK
Baek
Kwang-Hyun
KH
Yeo
Chang-Yeol
CY
Lee
Kwang-Youl
KY
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000235:genetics; D019943:Amino Acid Substitution; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D004789:Enzyme Activation / Q000235:genetics; D006801:Humans; D010766:Phosphorylation; D017354:Point Mutation; D011485:Protein Binding / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D048948:14-3-3 Proteins; D016159:Tumor Suppressor Protein p53; C482983:YWHAE protein, human; D017868:Cyclic AMP-Dependent Protein Kinases