MEKK3 interacts with the PA28 gamma regulatory subunit of the proteasome.

The proteasome is a multisubunit proteolytic enzyme comprising activator complexes bound to the 20 S catalytic core. The functions of the proteasomal activator (PA) 700 in ubiquitin/ATP-dependent protein degradation and of the PA28 alpha/beta activators in antigen presentation are well defined. However, the function of a third PA, PA28 gamma, ...
remains elusive. We now show that mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase kinase 3 (MEKK3), a MAPK kinase kinase (MAPKKK) involved in MAPK kinase 7 (MKK7)-c-Jun N-terminal kinase ('JNK') and MKK6-p38 signalling, can bind PA28 gamma but not PA28 alpha. In contrast, B-Raf, a MAPKKK specific for the MAPK/ERK kinase ('MEK')-ERK module, binds PA28 gamma and alpha. The PA28 gamma-binding domain of MEKK3 is located within its N-terminal regulatory domain (amino acids 1-178). Expression of MEKK3 in Cos-7 cells led to an increase in endogenous and co-expressed PA28 gamma protein levels, whereas kinase-deficient MEKK3 had no effect on PA28 gamma expression. Furthermore, in vitro assays indicated that PA28 gamma was a MEKK3 substrate. MEKK3 represents the first protein kinase capable of binding and phosphorylating a PA, and provides a potential mechanism to link stress-activated protein kinase signalling with the PA28 gamma-dependent proteasome.
Mesh Terms:
Animals, Autoantigens, Binding Sites, COS Cells, Cercopithecus aethiops, Cloning, Molecular, Cysteine Endopeptidases, MAP Kinase Kinase Kinase 3, MAP Kinase Kinase Kinases, Mitosis, Multienzyme Complexes, Mutagenesis, Nuclear Proteins, PC12 Cells, Phosphorylation, Polymerase Chain Reaction, Proteasome Endopeptidase Complex, Protein Subunits, Rats, Recombinant Proteins, Transfection
Biochem. J.
Date: Jul. 01, 2003
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