DIFFERENTIAL REGULATION OF GLYCOGEN-SYNTHASE KINASE-3-BETA BY PROTEIN-KINASE-C ISOTYPES

In cells, stimulation of protein kinase C (PKC) results in the dephosphorylation of specific residues proximal to the DNA binding domain of c-Jun, a major component of the AP-1 transcription factor. Since phosphorylation of this region of c-Jun inhibits interaction with DNA, this pathway may contribute to PKC activation of AP-1. To determine the mechanism(s) underlying this pathway, possible interactions between PKC and proteins implicated in c-Jun regulation are being investigated. Here it is shown that glycogen synthase kinase-3-beta (GSK-3-beta), a serine/threonine kinase that specifically targets the inhibitory c-Jun phosphorylation sites, is phosphorylated in vitro by particular forms of PKC (alpha, beta-1, gamma > beta-2; not epsilon). By contrast, the related GSK-3-alpha is not a substrate for any of these PKC isotypes. Phosphorylation of GSK-3-beta by PKC results in its specific inactivation. These results are consistent with a model in which activation of PKC stimulates c-Jun DNA binding by inhibiting its phosphorylation by GSK-3-beta.