Abstract
We demonstrate that POSH, a scaffold for the JNK signaling pathway, binds to Akt2. A POSH mutant that is unable to bind Akt2 (POSH W489A) exhibits enhanced-binding to MLK3, and this increase in binding is accompanied by increased activation of the JNK signaling pathway. In addition, we show that the association of MLK3 with POSH is increased upon inhibition of the endogenous phosphatidylinositol 3-kinase/Akt signaling pathway. Thus, the assembly of an active JNK signaling complex by POSH is negatively regulated by Akt2. Further, the level of Akt-phosphorylated MLK3 is reduced in cells expressing the Akt2 binding domain of POSH, which acts as a dominant interfering protein. Taken together, our results support a model in which Akt2 binds to a POSH-MLK-MKK-JNK complex and phosphorylates MLK3; phosphorylation of MLK3 by Akt2 results in the disassembly of the JNK complex bound to POSH and down-regulation of the JNK signaling pathway.
Highlights
The pro-survival effects of Akt are likely to be mediated in part through its regulation of the c-Jun N-terminal kinase (JNK) signaling pathway
A POSH mutant that is unable to bind Akt[2] exhibits increased binding to mixed lineage kinase 3 (MLK3). This increased binding of MLK3 to POSH is accompanied by increased activation of the JNK signaling pathway. Consistent with this observation, we find that the association of MLK3 with POSH is increased when the endogenous phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is inhibited with LY294002
These results indicate that the assembly of an active JNK signaling complex by POSH is negatively regulated by Akt[2]
Summary
The pro-survival effects of Akt are likely to be mediated in part through its regulation of the c-Jun N-terminal kinase (JNK) signaling pathway. The level of Akt-phosphorylated MLK3 is reduced in cells expressing the Akt[2] binding domain of POSH, which acts as a dominant interfering protein. These results indicate that the assembly of an active JNK signaling complex by POSH is negatively regulated by Akt[2].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
