title: MEKK2 kinase association with 14-3-3 protein regulates activation of c-Jun N-terminal kinase.
abstract: 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.
authors: From the Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.
authors: Adi E
authors: AE
authors: Matitau
authors: Timothy V
authors: TV
authors: Gabor
authors: R Montgomery
authors: RM
authors: Gill
authors: Michael P
authors: MP
authors: Scheid
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation; D019281:Dimerization; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048730:MAP Kinase Kinase Kinase 2 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D013912:Threonine / Q000737:chemistry
chemical_list: D048948:14-3-3 Proteins; D013912:Threonine; D048031:JNK Mitogen-Activated Protein Kinases; D048730:MAP Kinase Kinase Kinase 2; C482619:Map3k2 protein, mouse
keywords: Cell Proliferation; Gene Expression; Jun N-terminal Kinase (JNK); MAP Kinases (MAPKs); MEKK2; Signal Transduction
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