Characterization of S6K2, a novel kinase homologous to S6K1.
Rapamycin is an immunosuppressant which antagonizes cellular proliferation by inhibiting the function of mTOR. The mTOR:FKBP12: rapamycin complex blocks G1/S transition by inhibiting downstream targets essential for cell cycle progression. One such target is p70S6k1 (S6K1), a serine/threonine kinase which is inactivated by the mTOR : FKBP12 : rapamycin complex, and which has been linked to translational control by virtue of its ability to phosphorylate the ribosomal protein S6. In the current work, we describe cloning and characterization of a novel S6K1 homolog, p54 S6 kinase 2 (p54S6k2/S6K2). Similar to S6K1, S6K2 is activated by mitogens and by constitutively active PI3K, and is inhibited by rapamycin as well as wortmannin. Differences between activation of S6K1 and S6K2 by PDK1 were observed, suggesting potential differences in the regulation of these homologs. Strikingly, S6K2 activity and S6 phosphorylation were both intact in S6K1-/-ES cell, indicating a possible role for S6K2 in in vivo S6 phosphorylation. Interestingly, we found two isoforms of S6K2 which are localized to distinct cellular compartments; the smaller form resides in the detergent-soluble fraction, whereas the larger form is found in the particulate fraction. Our findings demonstrate the existence of a family of rapamycin-sensitive protein kinases potentially involved in S6 phosphorylation, translational control, and transduction of mTOR signals.
Lee-Fruman
K K
KK
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, MA 02115, USA.
Kuo
C J
CJ
Lippincott
J
J
Terada
N
N
Blenis
J
J
D002460:Cell Line; D020224:Expressed Sequence Tags; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics* / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D020123:Sirolimus / Q000494:pharmacology
D007527:Isoenzymes; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus