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AKT and 14-3-3 regulate Notch4 nuclear localization

Ramakrishnan, Gopalakrishnan; Davaakhuu, Gantulga; Chung, Wen Cheng; Zhu, He; Rana, Ajay; Filipovic, Aleksandra; Green, Andrew R.; Atfi, Azeddine; Pannuti, Antonio; Miele, Lucio; Tzivion, Guri


Gopalakrishnan Ramakrishnan

Gantulga Davaakhuu

Wen Cheng Chung

He Zhu

Ajay Rana

Aleksandra Filipovic

Azeddine Atfi

Antonio Pannuti

Lucio Miele

Guri Tzivion


Members of the Notch family of transmembrane receptors, Notch1-4 in mammals, are involved in the regulation of cell fate decisions and cell proliferation in various organisms. The Notch4 isoform, which is specific to mammals, was originally identified as a viral oncogene in mice, Int3, able to initiate mammary tumors. In humans, Notch4 expression appears to be associated with breast cancer stem cells and endocrine resistance. Following ligand binding, the Notch4 receptor undergoes cleavage at the membrane and the Notch4-intracellular domain (ICD), translocates to the nucleus and regulates gene transcription. Little is known on the mechanisms regulating Notch4-ICD and its nuclear localization. Here, we describe the identification of four distinct AKT phosphorylation sites in human Notch4-ICD and demonstrate that AKT binds Notch4-ICD and phosphorylates all four sites in vitro and in vivo. The phosphorylation in cells is regulated by growth factors and is sensitive to phosphatidyl inositol-3 kinase (PI3K) inhibitors. This phosphorylation generates binding sites to the 14-3-3 regulatory proteins, which are involved in the regulation of nucleocytoplasmic shuttling of target proteins, restricting phosphorylated Notch4-ICD to the cytoplasm. Our findings provide a novel mechanism for Notch4-ICD regulation, suggesting a negative regulatory role for the PI3K-AKT pathway in Notch4 nuclear signaling.


Ramakrishnan, G., Davaakhuu, G., Chung, W. C., Zhu, H., Rana, A., Filipovic, A., …Tzivion, G. (2015). AKT and 14-3-3 regulate Notch4 nuclear localization. Scientific Reports, 5(1), Article 8782.

Journal Article Type Article
Acceptance Date Feb 3, 2015
Online Publication Date Mar 5, 2015
Publication Date 2015-08
Deposit Date Oct 17, 2018
Publicly Available Date Oct 17, 2018
Journal Scientific Reports
Print ISSN 2045-2322
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 5
Issue 1
Article Number 8782
Public URL
Publisher URL