Redox-dependent dimerization of p38α mitogen-activated protein kinase with mitogen-activated protein kinase kinase 3

• DOI: 10.1074/jbc.m117.785410
• Publication Date: 2017-07-25T01:00:20Z
• Authors: Rekha Bassi; Joseph R. Burgoyne; Gian F. DeNicola; Olena Rudyk; Vittorio DeSantis; Rebecca L. Charles; Philip Eaton; Michael S. Marber
• Keywords: Dual-specificity phosphatase

The kinase p38α MAPK (p38α) plays a pivotal role in many biological processes. is activated by canonical upstream kinases that phosphorylate the activation region. purpose of our study was to determine whether such may depend on redox-sensing cysteines within p38α. and formed disulfide-bound heterodimer with MAP2K3 (MKK3) rat cardiomyocytes isolated hearts exposed H2O2. This disulfide sensitive reduction mercaptoethanol enhanced thioredoxin-reductase inhibitor auranofin. We predicted Cys-119 or Cys-162 p38α, close known MKK3 docking domain, were relevant for these redox characteristics. C119S mutation decreased whereas C162S increased dimer formation, suggesting two Cys residues act as vicinal thiols, consistent C119S/C162S being incapable sensing Similarly, formation abolished H9C2 cells expressing both subjected simulated ischemia reperfusion. However, mutants did not exhibit appreciable alteration activating dual phosphorylation. In contrast, anti-inflammatory agent 10-nitro-oleic acid (NO2-OA), component Mediterranean diet, reduced covalently modified Cys-119/Cys-162, probably obstructing access. Moreover, NO2-OA dephosphorylation hematopoietic tyrosine phosphatase (HePTP). Furthermore, steric obstruction Cys-119/Cys-162 pretreatment Langendorff-perfused murine prevented p38-MKK3 attenuated H2O2-induced contractile dysfunction. Our findings suggest cysteine sensors can dynamically regulate association between p38 MKK3.