Signal Transduction Pathways Involved in Phosphorylation and Activation of p70S6K Following Exposure to UVA Irradiation

Yiguo Zhang, Ziming Dong, Masaaki Nomura, Shuping Zhong, Nanyue Chen, Ann M. Bode, Zigang Dong

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

Abstract

Ultraviolet light A (UVA) plays an important role in the etiology of human skin cancer, and UVA-induced signal transduction has a critical role in UVA-induced skin carcinogenesis. The upstream signaling pathways leading to p70S6K phosphorylation and activation are not well understood. Here, we observed that UVA induces phosphorylation and activation of p70 S6K. Further, UVA-stimulated p70S6K activity and phosphorylation at Thr389 were blocked by wortmannin, rapamycin, PD98059, SB202190, and dominant negative mutants of phosphatidylinositol (PI) 3-kinase p85 subunit (DNM-Δp85), ERK2 (DNM.ERK2), p38 kinase (DNM-p38), and JNK1 (DNM-JNK1) and were absent in Jnk1-/- or Jnk2-/- knockout cells. The p70S6K phosphorylation at Ser411 and Thr 421/Ser424 was inhibited by rapamycin, PD98059, or DNM-ERK2 but not by wortmannin, SB202190, DNM-Δp85, or DNM-p38. However, Ser411, but not Thr421/Ser424 phosphorylation, was suppressed in DNM.JNK1 and abrogated in Jnk1-/- or Jnk2-/- cells. In vitro assays indicated that Ser411 on immunoprecipitated p70S6K proteins is phosphorylated by active JNKs and ERKs, but not p38 kinase, and Thr421/Ser424 is phosphorylated by ERK1, but not ERK2, JNKs, or p38 kinase. Moreover, p70S6K co-immunoprecipitated with PI 3-kinase and possibly PDK1. The complex possibly possessed a partial basal level of phosphorylation, but not at MAPK sites, which was available for its activation by MAPKs in vitro. Thus, these results suggest that activation of MAPKs, like PI 3-kinase/mTOR, may be involved in UVA-induced phosphorylation and activation of p70S6K.

Original languageEnglish (US)
Pages (from-to)20913-20923
Number of pages11
JournalJournal of Biological Chemistry
Volume276
Issue number24
DOIs
StatePublished - Jun 15 2001

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