UVA Induces Ser³⁸¹ Phosphorylation of p90 ^RSK/MAPKAP-K1 via ERK and JNK Pathways

UVA exposure plays an important role in the etiology of skin cancer. The family of p90-kDa ribosomal S6 kinases (p90^RSK/MAPKAP-K1) are activated via phosphorylation. In this study, results show that UVA-induced phosphorylation of p90^RSK at Ser³⁸¹ through ERKs and JNKs, but not p38 kinase pathways. We provide evidence that UVA-induced P90 ^RSK phosphorylation and kinase activity were time- and dose-dependent. Both PD98059 and a dominant negative mutant of ERK2 blocked ERKs and p90^RSK Ser³⁸¹ 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 UVA-induced Ser³⁸¹ phosphorylation of p90^RSK or kinase activity. UVA-induced p90^RSK phosphorylation and kinase activity were markedly attenuated in JnK₁-/- and JnK₂-/- cells. A dominant negative mutant of JNK₁ inhibited UVA-induced JNKs and p90 ^RSK phosphorylation and kinase activity, but had no effect on ERKs phosphorylation. PD169316, a novel inhibitor of JNKs and p38 kinase, inhibited phosphorylation of p90^RSK, JNKs, and p38 kinase, but not ERKs. However, SB202190, a selective inhibitor of p38 kinase, had no effect on p90^RSK or JNKs phosphorylation. Significantly, ERKs and JNKs, but not 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 of JNKs or ERKs, but not p38 kinase.