Abstract
Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1) is an important component in the stress-activated protein kinase pathway. Glutathione S-transferase Mu 1-1 (GST M1-1) has now been shown to inhibit the stimulation of MEKK1 activity induced by cellular stresses such as UV and hydrogen peroxide. GST M1-1 inhibited MEKK1 activation in a manner independent of its glutathione-conjugating catalytic activity. In vitro binding and kinase assays revealed that GST M1-1 directly bound MEKK1 and inhibited its kinase activity. Co-immunoprecipitation analysis showed a physical association between endogenous GST M1-1 and endogenous MEKK1 in L929 cells. Overexpressed GST M1-1 interfered with the binding of MEKK1 to SEK1 in transfected HEK293 cells. Furthermore, GST M1-1 suppressed MEKK1-mediated apoptosis. Taken together, our results suggest that GST M1-1 functions as a negative regulator of MEKK1.
Highlights
Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1),1 a 196-kDa serine/ threonine kinase, is one of the first identified members of the mitogen-activated protein kinase kinase kinases (MAP3Ks) [1,2,3,4,5]
We previously reported that Glutathione S-transferases (GSTs) M1-1 functions as an endogenous inhibitor of apoptosis signal-regulating kinase 1 (ASK1), a MAP3K of the JNK/SAPK and p38 mitogen-activated protein kinase pathways, thereby suppressing ASK1-mediated cell death [28]
To further understand the mechanism underlying the modulation of the JNK/SAPK signaling pathway by GST M1-1, we have investigated a possible effect of GST M1-1 on the components of this pathway and report in this study that GST M1-1 physically associates with MEKK1 and inhibits its kinase activity
Summary
Mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1),1 a 196-kDa serine/ threonine kinase, is one of the first identified members of the mitogen-activated protein kinase kinase kinases (MAP3Ks) [1,2,3,4,5]. We previously reported that GST M1-1 functions as an endogenous inhibitor of apoptosis signal-regulating kinase 1 (ASK1), a MAP3K of the JNK/SAPK and p38 mitogen-activated protein kinase pathways, thereby suppressing ASK1-mediated cell death [28]. To further understand the mechanism underlying the modulation of the JNK/SAPK signaling pathway by GST M1-1, we have investigated a possible effect of GST M1-1 on the components of this pathway and report in this study that GST M1-1 physically associates with MEKK1 and inhibits its kinase activity.
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