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  • Optical control of MAP kinase kinase 6 (MKK6) reveals that it has divergent roles in pro-apoptotic and anti-proliferative signaling.

Optical control of MAP kinase kinase 6 (MKK6) reveals that it has divergent roles in pro-apoptotic and anti-proliferative signaling.

The Journal of biological chemistry (2020-05-07)
Shah Md Toufiqur Rahman, Wenyuan Zhou, Alexander Deiters, Jason M Haugh
ABSTRACT

The selective pressure imposed by extrinsic death signals and stressors adds to the challenge of isolating and interpreting the roles of proteins in stress-activated signaling networks. By expressing a kinase with activating mutations and a caged lysine blocking the active site, we can rapidly switch on catalytic activity with light and monitor the ensuing dynamics. Applying this approach to MAP kinase 6 (MKK6), which activates the p38 subfamily of MAPKs, we found that decaging active MKK6 in fibroblasts is sufficient to trigger apoptosis in a p38-dependent manner. Both in fibroblasts and in a murine melanoma cell line expressing mutant B-Raf, MKK6 activation rapidly and potently inhibited the pro-proliferative extracellular signal-regulated kinase (ERK) pathway; to our surprise, this negative cross-regulation was equally robust when all p38 isoforms were inhibited. These results position MKK6 as a new pleiotropic signal transducer that promotes both pro-apoptotic and anti-proliferative signaling, and they highlight the utility of caged, light-activated kinases for dissecting stress-activated signaling networks.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
p38 MAP Kinase Inhibitor X, BIRB 796, The p38 MAP Kinase Inhibitor X, BIRB 796, also referenced under CAS 285983-48-4, controls the biological activity of p38 MAP Kinase. This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications.
Pricing and availability is not currently available.
Sigma-Aldrich
U0126, U0126, CAS 109511-58-2, is a potent and specific inhibitor of MEK1 (IC₅₀ = 72 nM) and MEK2 (IC₅₀ = 58 nM). The inhibition is noncompetitive with respect to both ATP and ERK.
Pricing and availability is not currently available.