Ubiquitin-dependent Regulation of Phospho-AKT Dynamics by the Ubiquitin E3 Ligase, NEDD4-1, in the Insulin-like Growth Factor-1 Response

Abstract

Background:After activation by phosphorylation, phospho-AKT (pAKT) is translocated to nucleus. Results: Ubiquitination of pAKT by NEDD4-1 is coupled to AKT activation at the plasma membrane by insulin-like growth factor (IGF)-1, which promotes pAKT nuclear trafficking. Conclusion: NEDD4-1 is an E3 ligase for pAKT specifically involved in pAKT nuclear trafficking in IGF-1 signaling. Significance: AKT activation and proper subcellular localization requires specific E3 ligases in a ligand-specific manner.

Nedd4-induced monoubiquitination of IRS-2 enhances IGF signalling and mitogenic activity

“…50). Nedd4 has also been reported to regulate the stability and subcellular localization of Akt and PTEN 17,51,52 . In our study, Nedd4 affected neither total nor cell-surface IGF-IR levels, and had little effect on the signalling downstream of IRS-1.…”

Akt SUMOylation Regulates Cell Proliferation and Tumorigenesis

“…For example, TRAF6 or SKP2-mediated K63 polyubiquitination at lysine residues in PH domain has been shown as an essential regulatory mechanism for Akt activation (15,16). Ubiquitination of Akt by CHIP, Nedd4, TTC3, and MULAN regulates Akt stability (17)(18)(19). Deacetylation of Akt at lysines in PH domain promotes its membrane translocation and activation (20).…”

Enhanced Phosphatidylinositol 3-kinase (PI3K)/Akt Signaling Has Pleiotropic Targets in Hippocampal Neurons Exposed to Iron-induced Oxidative Stress

“…After membrane anchoring, Akt is phosphorylated sequentially by phosphoinositide-dependent kinase 1 (PDK-1) at threonine 308 and by the mammalian target of rapamycin complex 2 (mTORC2) at serine 473 (5). Upon phosphorylation, Akt translocates from the plasma membrane to intracellular compartments, including the cytoplasm and nucleus, where it phosphorylates a variety of substrates (6). One of these substrates is glycogen synthase kinase 3␤ (GSK3␤), which is inhibited through phosphorylation at serine 9 by Akt (3).…”