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Nuclear trafficking of PDK1 in importin7-dependent manner is required for insulin-induced AKT ubiquitination
Fangdi Wang1, Li Hu2, Xingyue Zeng1
1School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China.
Abstract:
AKT is a pivotal kinase involved in diverse cellular processes, including tumorigenesis and glycogen metabolism. Ubiquitination modification of AKT has been reported as a critical cellular event that regulates its kinase activity and membrane translocation; however, the molecular mechanisms involved in AKT ubiquitination remain elusive. Here, we employed loss-of-function approaches and mutants of PDK1 with altered phosphorylation and modified nucleocytoplasmic shuttling behaviors to identify the functional roles of PDK1 on the ubiquitination of AKT. Our findings reveal that the nuclear entry of PDK1 in an importin7-dependent manner is required for insulin-induced TRAF6-mediated ubiquitination of AKT, which has been previously shown to occur in the nucleus. Moreover, the phosphorylation of PDK1 at S241 and the PI3K-mediated phosphorylation of PDK1 at S396 both regulate AKT ubiquitination by controlling nuclear entry of PDK1. These results provide new insights into the control of AKT signaling and suggest potential avenues for developing targeted AKT-modulating therapeutics.
Insights
Nuclear entry of PDK1 is crucial for AKT ubiquitination, a key event in cell signaling. This process, regulated by PDK1 phosphorylation, offers new therapeutic targets for AKT-related diseases.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Biochemistry
Background:
- AKT is a key kinase regulating tumorigenesis and metabolism.
- AKT ubiquitination controls its activity and localization, but mechanisms are unclear.
Purpose of the Study:
- To elucidate the role of PDK1 in AKT ubiquitination.
- To identify molecular mechanisms governing AKT ubiquitination.
Main Methods:
- Loss-of-function approaches.
- Utilized PDK1 mutants with altered phosphorylation and nucleocytoplasmic shuttling.
- Investigated importin7-dependent nuclear entry of PDK1.
Main Results:
- Nuclear entry of PDK1 is essential for TRAF6-mediated AKT ubiquitination.
- PDK1 phosphorylation at S241 and PI3K-mediated phosphorylation at S396 regulate PDK1 nuclear import.
- Insulin signaling triggers this nuclear import-dependent ubiquitination pathway.
Conclusions:
- PDK1's nuclear translocation is a critical regulatory step for AKT ubiquitination.
- Phosphorylation events on PDK1 fine-tune AKT ubiquitination via nuclear entry.
- Findings provide novel insights into AKT signaling control and therapeutic strategies.
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