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ToxSci Advance Access first published online on September 1, 2004
This version published online on September 8, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh273
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received July 8, 2004
Accepted August 25, 2004

Systems Toxicology

Toxin-Induced Tail Phosphorylation of Hepatocellular S6 Kinase: Evidence for a Dual Involvement of the AMP-Activated Protein Kinase in S6 Kinase Regulation

Michael T. N. Møller 1, Hamid R. Samari 1, and Per O. Seglen 1*

1 Proteomics & Mammalian Cell Biology Section, Department of Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway

* To whom correspondence should be addressed. E-mail: p.o.seglen{at}imbv.uio.no.


  Abstract

Several protein phosphatase-inhibitory toxins (okadaic acid, microcystin, calyculin A, cantharidin, tautomycin) administered to isolated rat hepatocytes were found to induce phosphorylation in the tail region of S6 kinase (S6K; p70S6K1) as detected with a phosphospecific antibody against doubly phosphorylated Thr-421/Ser424. AICAR, an adenosine analogue that elicits activation of the hepatocellular AMP-activated protein kinase (AMPK), similarly stimulated S6K tail phosphorylation. The flavonoid naringin prevented the effects of AICAR, okadaic acid and microcystin on AMPK activation as well as on S6K tail phosphorylation, suggesting AMPK as a mediator of the latter. The effects of AICAR and the toxins were rapamycin-resistant; in contrast, amino acids induced an S6K tail phosphorylation that was rapamycin-sensitive, suggesting mediation by the protein kinase mTOR. Amino acids activated S6K by phosphorylation at Thr-389, but the toxins did not, and AICAR in fact suppressed the activating phosphorylation induced by the amino acids. The possibility thus must be considered that the phosphorylated S6K tail may transmit a toxin-induced signal independently of S6K enzymatic activity. Despite their inability to activate S6K, the toxins (but not AICAR) stimulated phosphorylation of the ribosomal protein S6, presumably by activating some other S6-phosphorylating protein kinase.

Keywords: rat; liver; hepatocyte; okadaic acid; microcystin; calyculin A; cantharidin; tautomycin; naringin; AICAR; S6 kinase; AMP-activated protein kinase.
Note: In this version of this article, figure 13 has been corrected.
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