MEKK2 Kinase Association with 14-3-3 Protein Regulates Activation of c-Jun N-terminal Kinase

• Published in: The Journal of biological chemistry 2013-09, Vol.288 (39), p.28293-28302
• Main Authors: Matitau, Adi E., Gabor, Timothy V., Gill, R. Montgomery, Scheid, Michael P.
• Format: Article
• Language: English
• Subjects: 14-3-3 Proteins - metabolism; Animals; Binding Sites; Cell Proliferation; Dimerization; Fibroblasts - metabolism; Gene Expression; Gene Expression Regulation, Enzymologic; JNK Mitogen-Activated Protein Kinases - metabolism; Jun N-terminal Kinase (JNK); MAP Kinase Kinase Kinase 2 - metabolism; MAP Kinase Signaling System; MAP Kinases (MAPKs); MEKK2; Mice; Phosphorylation; Protein Binding; Signal Transduction; Threonine - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.511352

MEKK2 (MAP/ERK kinase kinase-2) is a serine/threonine kinase that belongs to the MEKK/STE11 family of MAP kinase kinase kinases (MAP(3)Ks). MEKK2 integrates stress and mitogenic signals to the activation of NF-κB, JNK1/2, p38, and ERK5 pathways. We have found that MEKK2 is regulated through a phosphorylation-dependent association with 14-3-3, a group of adapters that modulate dimerization and association between proteins. We found that MEKK2 was phosphorylated at Thr-283, which resulted in decreased activation loop phosphorylation at Ser-519 and consequently reduced activity. Mechanistically, we found that MEKK2 associated with inactive MEKK2 in the absence of 14-3-3 binding, which led to trans-autophosphorylation of Ser-519. Enforced binding with 14-3-3 reduced Ser-519 trans-autophosphorylation. Expression of T283A MEKK2 within a MEKK2−/− background enhanced stress-activated c-Jun N-terminal kinase activity while elevating IL-6 expression, but also reduced ERK activation with a corresponding reduced proliferation rate. These results indicate that Thr-283 phosphorylation is an important regulatory mechanism for MEKK2 activation. Background: MEKK2 is an important kinase involved in the activation of MAPK pathways. Results: MEKK2 binds to 14-3-3 in a phosphorylation-dependent manner. This reduced its phosphorylation at an activating site. Conclusion: MEKK2 remains inactive until it is dephosphorylated at Thr-283, which releases 14-3-3 and allows autophosphorylation and activation of JNK. Significance: Binding of 14-3-3 to MEKK2 provides a mechanism for reducing activity and directing signal specificity.