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      Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulin-like growth factor-1 response.

      The Journal of Biological Chemistry

      Animals, Cell Line, Tumor, Cell Membrane, metabolism, Cell Nucleus, Cytoplasm, Endosomal Sorting Complexes Required for Transport, deficiency, genetics, Fibroblasts, cytology, Gene Expression Regulation, Humans, Insulin-Like Growth Factor I, Mice, Phosphorylation, Proteasome Endopeptidase Complex, Protein Transport, Proto-Oncogene Proteins c-akt, Ubiquitination, Signal Transduction, Transfection, Ubiquitin, Ubiquitin-Protein Ligases

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          Abstract

          AKT is a critical effector kinase downstream of the PI3K pathway that regulates a plethora of cellular processes including cell growth, death, differentiation, and migration. Mechanisms underlying activated phospho-AKT (pAKT) translocation to its action sites remain unclear. Here we show that NEDD4-1 is a novel E3 ligase that specifically regulates ubiquitin-dependent trafficking of pAKT in insulin-like growth factor (IGF)-1 signaling. NEDD4-1 physically interacts with AKT and promotes HECT domain-dependent ubiquitination of exogenous and endogenous AKT. NEDD4-1 catalyzes K63-type polyubiquitin chain formation on AKT in vitro. Plasma membrane binding is the key step for AKT ubiquitination by NEDD4-1 in vivo. Ubiquitinated pAKT translocates to perinuclear regions, where it is released into the cytoplasm, imported into the nucleus, or coupled with proteasomal degradation. IGF-1 signaling specifically stimulates NEDD4-1-mediated ubiquitination of pAKT, without altering total AKT ubiquitination. A cancer-derived plasma membrane-philic mutant AKT(E17K) is more effectively ubiquitinated by NEDD4-1 and more efficiently trafficked into the nucleus compared with wild type AKT. This study reveals a novel mechanism by which a specific E3 ligase is required for ubiquitin-dependent control of pAKT dynamics in a ligand-specific manner.

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          Author and article information

          Journal
          23195959
          3548477
          10.1074/jbc.M112.416339

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