Cloning and characterization of a nuclear S6 kinase, S6 kinase-related kinase (SRK); a novel nuclear target of Akt.
Akt is stimulated by several growth factors, and mediates their cell survival signals. Recent studies have shown that Akt may play an intermediate role between phosphatidylinositol 3-kinase (PI3K) and p70 S6 kinase (p70S6K). Here we show that a novel nuclear p70S6K-related kinase (SRK) exists and that its in vivo function is also augmented by over-expression of Akt. Conceptual translation of the SRK cDNA revealed that the catalytic domain of SRK was highly homologous to that of p70S6K, and that the treatment of wortmannin or rapamycin strongly inhibited the phosphorylation and the activation of SRK, as in p70S6K. However, the N- and C-terminal domains of SRK were quite different from those of p70S6K. In immunolocalization analyses, we demonstrated a constitutive nuclear localization of SRK and the presence of a nuclear localization signal in its C-terminus. In vitro S6 phosphotransferase activities of SRK were stimulated with a slower kinetics by a variety of agonists to p70S6K. Interestingly, over-expression of the proto-oncogene Akt resulted in EGF-independent activation of SRK, while over-expression of kinase-dead Akt actually had an inhibitory effect. This relationship between Akt and SRK suggests that SRK may be a novel target of Akt and perhaps an important downstream component in the nuclear function of Akt.
Koh
H
H
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Kusong-dong, Yusong, Taejon 305-701, Korea.
Jee
K
K
Lee
B
B
Kim
J
J
Kim
D
D
Yun
Y H
YH
Kim
J W
JW
Choi
H S
HS
Chung
J
J
D020134:Catalytic Domain; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology*; D003001:Cloning, Molecular; D018076:DNA, Complementary; D006801:Humans; D008969:Molecular Sequence Data; D051058:Oncogene Protein v-akt; D000090063:Proto-Oncogene Mas; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics* / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology; D013379:Substrate Specificity
D018076:DNA, Complementary; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D015682:Retroviridae Proteins, Oncogenic; D051058:Oncogene Protein v-akt; D019893:Ribosomal Protein S6 Kinases