Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2

Previous studies demonstrated that in vitro the protein kinase TAO2 activat es MAP/ERK kinases (MEKs) 3, 4, and 6 toward their substrates p38 MAP kinas e and c-dun N-terminal kinase/stress-activated protein kinase (JNK/SAPK). I n this study, we examined the ability of TAO2 to activate stress-sensitive MAP kinase pathways in cells and the relationship between activation of TAO 2 and potential downstream pathways. Over-expression of TAO2 activated endo genous JNK/SAPK and p38 but not ERK1/2. Cotransfection experiments suggeste d that TAO2 selectively activates MEK3 and MEK6 but not MEKs 1, 4, or 7. Co immunoprecipitation demonstrated that endogenous TAO2 specifically associat es with MEK3 and MEK6 providing one mechanism for preferential recognition of MEKs upstream of p38. Sorbitol, and to a lesser extent, sodium chloride, Taxol, and nocodazole increased TAO2 activity toward itself and kinase-dea d MEKs 3 and 6, Activation of endogenous TAO2 during differentiation of C2C 12 myoblasts paralleled activation of p38 but not JNK/SAPK, consistent with the idea that TAO2 is a physiological regulator of p38 under certain circu mstances.