High impact information on MAP3K2

• We generated an anti-p-MEKK2/3 antibody and used this antibody to demonstrate that lipopolysaccharide induced MEKK2 and MEKK3 phosphorylation on their regulatory serine [1].
• Identification of MEKK2/3 serine phosphorylation site targeted by the Toll-like receptor and stress pathways [1].
• Mutation of this serine to an alanine severely impaired MEKK2/3 activation [1].
• MKK7 is activated in response to cross-linking of FcepsilonRI, and this activation is inhibited by MAP/ERK kinase (MEK) kinase 2 (MEKK2) gene disruption [2].
• MEK5 is the only MAP2K to express a PB1 domain, and we have shown that it heterodimerizes with the PB1 domain of MEKK2 [3].

Biological context of MAP3K2

• In this study, we demonstrated that MAP3K MEKK2 activation requires dimerization [4].
• Dimerization through the catalytic domain is essential for MEKK2 activation [4].
• A set of chimeric molecules were generated and the loss of activity in Triton X-100 mapped to kinase domain II/III and specifically to serine 390 of MEKK3 and valine 384 of MEKK2, residues immediately N-terminal to the active site lysine [5].

Associations of MAP3K2 with chemical compounds

• We mapped the MEKK2 dimerization motif in its catalytic domain and showed that the NH2-terminal region is not required for MEKK2 dimer formation [4].
• In vitro activity of MEKK2 and MEKK3 in detergents is a function of a valine to serine difference in the catalytic domain [5].

Regulatory relationships of MAP3K2

• Furthermore, MEKK2 immunoprecipitates activated c-Jun in an IL-1 dependent manner and this activity was inhibited by the selective JNK inhibitor SP600125 [6].

Other interactions of MAP3K2

• No scaffold protein was required for the MEKK2-JNKK2-JNK1 tripartite-complex formation [7].
• Moreover, both MEKK2 and MEKK3 coimmunoprecipitated with endogenous WNK1 from cell lysates [8].
• WNK1 activates ERK5 by an MEKK2/3-dependent mechanism [8].
• The biological roles of MEKK2, 3 and 4 are under investigation and undoubtedly homologous deletion of these MEKK family members will be invaluable at determining the biological functions of these MEKKs [9].
• In contrast, MEKK2 and PKA also increased shedding of TNF receptor 2, suggesting that these kinases contribute to a general program regulating ectodomain shedding [10].

References