to see a detailed, interactive version of this map NOTE: PathFinder requires the Flash plug-in for proper viewing. It will launch in a separate pop-up window, please turn off any pop-up blockers for this web site. Copyright ©2006 ProteinLounge.com

 P70S6K Signaling

The p70S6K signaling pathway involves the regulation and downstream effectors of two forms of S6K (p70-ribosomal S6 kinase): S6Kα (S6Kα) (S6KI) and S6Kβ (S6Kβ (S6K2). S6Kα and S6Kβ each exist as alternative gene splicing variants; S6KαI and S6KβI are nuclear forms, whereas S6KαII and S6KβII are predominantly, but not exclusively, cytoplasmic forms. One level of regulation of S6KαII and S6KβII activity may involve shuttling between the nucleus and the cytoplasm. The primary activation of S6Ks involves hierarchical phosphorylation of multiple Ser/Thr sites, primarily by the rapamycin-sensitive pathway involving PDK1; Akt/PKB; mTOR/FRAP. Activation of S6Ks by Akt/PKB; mTOR/FRAP is negatively regulated by atypical PKCs, such as PKCzeta. Classical and novel PKCs appear to activate S6Ks. This activation may actually involve translocation of specific variant active S6K(s) from the nucleus to the cytoplasm.

P70S6K promotes protein synthesis and cell survival. Active S6K(s) phosphorylates important downstream effectors of protein synthesis such as S6, a subunit of the 40 ribosome; cap-binding protein (CBP) (eIF4E), a component of the eIF4F initiation complex and eEF2Kinase, which phosphorylates eEF2. Phosphorylation of S6 promotes TOP-mRNA class translation initiation, phosphorylation of CBP promotes its interaction with 48 S ribosome and global mRNA translation, and phosphorylation of eEF2kinase inhibits the kinase allowing eEF2 to become dephosphorylated and activated. Consequently, p70S6K promotes protein synthesis. P70S6K also promotes survival. Active S6K(s) phosphorylates BAD at Ser-136. BAD is a pro-apoptotic factor which is bound by 14-3-3 protein in its Ser-136 phosphorylated form. BAD is neutralized when it is bound to 14-3-3.