Nuclear trafficking of PDK1 in importin7-dependent manner is required for insulin-induced AKT ubiquitination
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.
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