【研究进展】NEDD4-1通过泛素化调控AKT激活和入核

关于AKT的激活调控机制是很多战友所关心的话题，但相关文献不是很多。这里有一篇会议摘要介绍了akt激活的新机制，希望对有关战友有帮助。

Ubiquitination Of AKT By NEDD4-1 Regulates AKT Activation And Trafficking To Nucleus

Chuan-dong Fan,

Michelle Lum, Jennifer Black and Xinjiang Wang

Department of Pharmacology & Therapeutics

Roswell Park Cancer Institute, Buffalo, NY, USA

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 translocation to its action sites remain unclear. Here we show that NEDD4-1 is a novel E3 ligase specifically regulating ubiquitin-dependent trafficking of phospho-AKT in IGF-1 signaling. NEDD4-1 promotes ubiquitination of exogenous and endogenous AKT requiring the HECT domain of NEDD4-1. Plasma membrane binding is the key step for AKT ubiquitination by NEDD4-1. Ubiquitinated phospho-AKT translocates to perinuclear regions, where it is either released into the cytoplasm, imported into the nucleus or coupled with proteasomal degradation. IGF-1 signaling only stimulates NEDD4-1-mediated ubiquitination of phospho-AKT without altering total AKT ubiquitination. A cancer- derived plasma membrane-philic mutant AKT(E17K) is better ubiquitinated by NEDD4-1 and more efficiently trafficked into nucleus compared to wild type AKT. This study reveals a novel mechanism by which a specific E3 ligase is required for ubiquitin-dependent control of phosphor-AKT dynamics in a ligand- specific manner.



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SCIENCE RETREAT - Roswell Park Cancer Institute

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Jul 20, 2012 – Ubiquitination Of AKT By NEDD4-1. Regulates AKT Activation And. Trafficking To Nucleus. Chuan-dong Fan, Michelle Lum, Jennifer Black ...