p38 mitogen activated protein kinase. Do we need a new therapeutic strategy?

p38α mitogen-activated protein kinase (p38α) is abundant in the heart and activated by stresses such as ischaemia and neurohormones. Preclinically, inhibition of p38α reduces injury and improves cardiac function. Early clinical trials also suggest protection but have raised significant concerns of liver, skin and renal toxicity. p38α is expressed in every cell type. However, its mechanism of activation in the heart during myocardial ischaemia is very unusual as binding to a scaffold protein known as TAB1 induces p38α autoactivation by phosphorylation of its own activation loop. This differs markedly from the usual mechanism of activation whereby upstream kinases activate the kinase by transphosphorylation. Within this review we highlight the forms of p38 activation and if the TAB1-mediated mechanism is worthy of a drug discovery effort now that the crystal structure is defined.