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

作者：Matitau Adi E; Gabor Timothy V; Gill R Montgomery; Scheid Michael P^*

来源：Journal of Biological Chemistry, 2013, 288(39): 28293-28302.

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-kappa B, 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.

• 出版日期2013-9-27