Characterization of the Mitogen-activated Protein Kinase Kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 Pathways Regulated by MEK Kinases 2 and 3

Abstract

We previously reported the isolation of cDNAs encoding two mammalian mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) kinase kinases, designated MEKK2 and MEKK3 (Blank, J.L., Gerwins, P., Elliott, E.M., Sather, S. These data indicate that MKK3 is preferentially activated by MEKK3, whereas MKK4 is activated both by MEKK2 and MEKK3. Consistent with these observations, MEKK2 and MEKK3 also activated JNK1 in vivo. However, MEKK3 failed to activate p38 when coexpressed in either the absence or presence of MKK3, indicating that MEKK3 is not coupled to p38 activation in vivo. These observations suggest that regulation of p38 and JNK1 pathways by MEKK3 may involve distinct mechanisms to prevent p38 activation but to allow JNK1 activation.

New insights into the biogenesis of nuclear RNA polymerases?This paper is one of a selection of papers published in this special issue entitled “Canadian Society of Biochemistry, Molecular & Cellular Biology 52nd Annual Meeting — Protein Folding: Principles and Diseases” and has undergone the Journal's usual peer review process.

“…MAP(3)Ks participate in the early steps of a signal transduction pathway that will promote various cellular processes in responses to a number of external stimuli through a sequential MAP(3)K > MAP(2)K > MAPK phosphorylation cascade (Chang and Karin 2001;Pearson et al 2001). In accordance to this general scheme, MEKK3 is known to phosphorylate a number of MAP(2)K (MEK/MKK1-7), which leads to the activation of their specific downstream MAPK (ERK1/2, JNK/SAPK, ERK5, and p38) (Blank et al 1996;Deacon and Blank 1997;Ellinger-Ziegelbauer et al 1997;Chao et al 1999;Deacon and Blank 1999;Uhlik et al 2003). MEKK3 is also involved in the NF-κB pathway where it activates the IKK complex in response to TNFα and LPS (Yang et al 2001;Schmidt et al 2003;Samanta et al 2004).…”

MAP3Ks as central regulators of cell fate during development

“…4) (Deacon and Blank, 1997;Uhlik et al, 2003;Fritz et al, 2006). More recent evidence suggests that it also regulates activities of ERK5 (Chao et al, 1999) and the transcription factor, NF B (Zhao and Lee, 1999;Yang et al, 2001).…”

Thioredoxin Activates MKK4-NFκB Pathway in a Redox-dependent Manner to Control Manganese Superoxide Dismutase Gene Expression in Endothelial Cells

“…As shown in Fig. 4D, increasing (31), we determined whether this autophosphorylation could be increased in the presence of reduced Trx. It is plausible that Trx might directly reduce the Cys-246 and Cys-266 due to its thiol-reducing activity, and it could thus induce autophosphorylation of MKK4 on Thr-261 or Ser-257.…”

“…Trx Directly Activates MKK4 without the Involvement of MEKK1 in ECs-MEKK1 is an upstream kinase that phosphorylates MKK4/MKK7 leading to their activation (31). Studies have shown that Cys-1238 in MEKK1 is redox-sensitive, and the glutathionylation of this residue inhibits MEKK1 activation (36).…”