The proto-oncogene c-jun is a component of the AP-1 transcription factor family involved in the mediation of nuclear events elicited by extracellular stimuli. The c-jun protein is negatively regulated by phosphorylation of residues near the carboxy terminus which are dephosphorylated in response to phorbol esters. Here we identify two serine residues in the amino terminal A1 transactivation domain which are phosphorylated in response to a variety of mitogens, phorbol esters and activated ras. We present evidence that mitogen-activated protein-serine (MAP) kinases (pp54 and pp42/44) specifically phosphorylate these sites and that their phosphorylation positively regulates the transacting activity of c-jun. The MAP kinase enzymes pp54 and pp42/44 are regulated by tyrosine as well as serine/threonine phosphorylation. MAP kinase activation of c-jun may underlie the common stimulation of this transcription factor by mitogens, growth factors and oncogenes.

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Molecular cloning of glycogen synthase kinase‐3 (GSK‐3) has demonstrated the existence of a novel form, termed GSK‐3β, which is highly related to the well characterised GSK‐3α protein but derived from a distinct gene. The cDNA cloning also revealed a striking degree of amino acid identity between the two GSK‐3 proteins, particularly the β‐form, and the zeste‐white3/shaggy (zw3sgg) homeotic gene of Drosophila melanogaster. Abrogation of zw3sgg causes pleiotropic effects on fruitfly development affecting segmental organisation and cell fate determination. In view of the potential importance of GSK‐3β in mammalian development and the lack of previous characterisation, we have expressed this protein in insect cells using recombinant baculovirus. A rapid purification scheme has been developed yielding essentially pure GSK‐3β protein in three chromatographic steps. The protein has autonomous protein kinase activity and similar, but not identical, substrate preferences to GSK‐3α. Both GSK‐3 proteins activate the MgATP‐dependent form of protein phosphatase‐1 and thus display ‘factor A’ activity. Since GSK‐3β exhibits an identical site specificity to GSK‐3α with respect to phosphorylation of the proto‐oncogene/transcription factors c‐jun and c‐myc, it is likely that the Drosophila zw3sgg protein kinase has a similar specificity for such transcription factors which may underlie the pleiotropic phenotypes observed when the Drosophila homologue is mutationally inactivated.