Regulation of the Proto-oncogene Product c-Jun by Phosphorylation-Mediated Intramolecular Signaling

The biological function of the proto-oncogene product c-Jun as a transcription factor (AP-1 constituent) has been reported to be regulated by complex phosphorylation events in different parts of the protein. The first phosphorylation event that was characterized in detail involved a cluster of COOH-terminal residues in direct neighborhood to the DNA-binding domain. It was shown that threonine 231, serine 243, and serine 249 (referred to here as ‘COOH-terminal cluster’) are phosphorylated in resting cells with low c-Jun activity, whereas in cells that were stimulated by the addition of growth factors or phorbol ester tumor promoters (e.g. TPA, an agonist of protein kinase C (PKC)) or by introduction of activated alleles of Ras this phosphorylation decreases [Boyle et al., 1991; Papavassiliou et al., 1992]. Comparison of the DNA-binding potential of phosphorylated and non-phosphorylated forms of c-Jun revealed that these phosphorylations preclude DNA binding [Boyle et al., 1991; Papavassiliou et al., 1992]. The mechanism of this inhibition is unclear but it seems plausible that the extra negative charges on c-Jun in close proximity to the DNA-binding domain would cause an electrostatic repulsion between the protein molecule and the acidic phosphate groups of the target DNA sequence [Hurley et al., 1990]. It was postulated that dephosphorylation of c-Jun in the COOH-terminal cluster follwing mitogenic activation of cells was the effect of a singal-induced phosphatase or a down-regulated kinnase or both, i.e. a primary event of c-Jun activation [Karin, 1994].