UVA induces Ser(381) phosphorylation of p90(RSK)/MAPKAP-K1 via ERK and JNKpathways

UVA exposure plays an important role in the etiology of skin cancer. The fa mily of p90-kDa ribosomal S6 kinases (p90(RSK)/MAPKAP-K1) are activated via phosphorylation, In this study, results show that UVA-induced phosphorylat ion of p90(RSK) at Ser(381) through ERKs and JNKs, but not p38 kinase pathw ays. We provide evidence that UVA-induced p90(RSK) phosphorylation and kina se activity were time- and dose-dependent. Both PD98059 and a dominant nega tive mutant of ERK2 blocked ERKs and p90(RSK) Ser(381) phosphorylation, as well as p90(RSK) activity. A dominant negative mutant of p38 kinase blocked UVA-induced phosphorylation of p38 kinase, but had no effect on WA-induced Ser(381) phosphorylation of p90(RSK) or kinase activity. UVA-induced p90(R SK) phosphorylation and kinase activity were markedly attenuated in JnK(1)- /- and JnK(2)-/- cells. A dominant negative mutant of JNK(1) inhibited UVA- induced JNKs and p90(RSK) phosphorylation and kinase activity, but had no e ffect on ERKs phosphorylation, PD169316, a novel inhibitor of JNKs and p38 kinase, inhibited phosphorylation of p90(RSK), JNKs, and p38 kinase, but no t ERKs. However, SB202190, a selective inhibitor of p38 kinase, had no effe ct on p90(RSK) gp JNKs phosphorylation. Significantly, ERKs and JNKs, but n ot p38 kinase, immunoprecipitated with p90(RSK) when stimulated by UVA and p90(RSK) was a substrate for ERK2 and JNK2, but not p38 kinase. These data indicate clearly that p90(RSK) Ser381 may be phosphorylated by activation o f JNKs or ERKs, but not p38 kinase.