A stress-activated kinase cascade can mediate the activation of tyrosine hydroxylase in chromaffin cells.

Tyrosine hydroxylase (TH) catalyses the initial, rate-limiting step in catecholamine biosynthesis and is therefore responsible for replenishing the stocks of adrenalin and noradrenalin in the adrenal medulla which are depleted following release of these hormones into the circulation. TH is activated in vitro and in vivo by phosphorylation and various kinases have been shown to phosphorylate four sites on this enzyme [l-41. We were interested to investigate whether a novel stress-activated kinase cascade [5 ] could mediate the phosphorylation and activation of TH. This cascade is triggered by exposure of cells to cellular stresses and inflammatory cytokines (Fig 1) and is analogous to, but distinct from, the ‘classical’ growth factor-activated MAP kinase cascade. Study of the roles of the novel cascade is facilitated by the use of SB 203580 [6], a specific inhibitor of SAPK-2, a MAP kinase homologue in the novel cascade. Physiological targets for the cascade identified using this inhibitor include the small heat shock protein HSP27 and the transcription factor CREB.