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 surviv al signals. Recent studies have shown that Akt may play an intermediate rol e between phosphatidylinositol 3-kinase (PI3K) and p70 S6 kinase (p70S6K), Here we show that a novel nuclear p70S6K-related kinase (SRK) exists and th at its in vivo function is also augmented by over-expression of Akt, Concep tual translation of the SRK cDNA revealed that the catalytic domain of SRK was highly homologous to that of p70S6K, and that the treatment of wortmann in or rapamycin strongly inhibited the phosphorylation and the activation o f SRK, as in p70S6K, However, the Nand C-terminal domains of SRK were quite different from those of p70S6K. In immunolocalization analyses, we demonst rated a constitutive nuclear localization of SRK and the presence of a nucl ear localization signal in its C-terminus, In vitro S6 phosphotransferase a ctivities of SRK were stimulated with a slower kinetics by a variety of ago nists to p70S6K, Interestingly, overexpression of the proto-oncogene Akt re sulted in EGF-independent activation of SRK, while over-expression of kinas e-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 impo rtant downstream component in the nuclear function of Akt.