THE STRESS-ACTIVATED PROTEIN-KINASE SUBFAMILY OF C-JUN KINASES

THE mitogen-activated protein (MAP) kinases Erk-1 and Erk-2 are prolin e-directed kinases that are themselves activated through concomitant p hosphorylation of tyrosine and threonine residues(1-4). The kinase p54 (M(r) 54,000), which was first isolated from cycloheximide-treated ra ts, is proline-directed like Erks-1/2, and requires both Tyr and Ser/T hr phosphorylation(3,5,6) for activity. p54 is, however, distinct from Erks-1/2 in its substrate specificity, being unable to phosphorylate pp90(rsk) but more active in phosphorylating the c-Jun transactivation domain(5,7,8). Molecular cloning of p54 reveals a unique subfamily of extracellularly regulated kinases. Although they are 40-45% identical in sequence to Erks-1/2, unlike Erks-1/2 the p54s are only poorly act ivated in most cells by mitogens or phorbol esters. However, p54s are the principal c-Jun N-terminal kinases activated by cellular stress an d tumour necrosis factor (TNF)-alpha, hence they are designated stress -activated protein kinases, or SAPKs. SAPKs are also activated by sphi ngomyelinase, which elicits a subset of cellular responses to TNF-alph a (ref. 9). SAPKs therefore define a new TNF-alpha and stress-activate d signalling pathway, possibly initiated by sphingomyelin-based second messengers, which regulates the activity of c-Jun.