AKT and 14-3-3 Regulate Notch4 Nuclear Localization

Gopalakrishnan, Ramakrishnan; Davaakhuu, Gantulga; Chung, W. C.; Zhu, He; Rana, Ajay; Filipović, Aleksandra; Green, Andrew; Atfi, Azeddine; Pannuti, Antonio; Miele, Lucio; Tzivion, Guri

doi:10.1038/srep08782

Cited by 24 publications

(27 citation statements)

References 38 publications

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“…Akt can regulate Notch activity via a direct or indirect function. For example, Akt functions upstream of Notch in aortic endothelial cells (Konantz et al, 2016), can directly phosphorylate Notch4-ICD (Lee et al, 2014) and regulate Notch4 nuclear localization (Ramakrishnan et al, 2015). Alternatively, angiopoietin-1 can activate Akt and promotes Notch signaling indirectly by phosphorylating glycogen synthase kinase 3b (GSK3b), thereby enhancing b-catenin activity and upregulating Dll4-Notch in endothelial cells Zhang et al, 2011b).…”

Section: Discussionmentioning

confidence: 99%

Akt is required for artery formation during embryonic vascular development

Zhou

Ristori

et al. 2020

Preprint

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One of the first events in the development of the cardiovascular system is morphogenesis of the main embryonic artery, the dorsal aorta (DA). The DA forms via a conserved genetic process mediated by the migration, specification, and organization of endothelial progenitor cells into a distinct arterial lineage and vessel type. Several angiogenic factors activate different signaling pathways to control DA formation, however the physiological relevance of distinct kinases in this complex process remains unclear. Here, we identify the role of Akt during early vascular development by generating mutant zebrafish lines that lack expression of akt isoforms. Live cell imaging coupled with single cell RNA sequencing of akt mutants reveal that Akt is required for proper development of the DA by sustaining arterial cell progenitor specification and segregation. Mechanistically, inhibition of active FOXO in akt mutants rescues impaired arterial development but not the expression of arterial markers, whereas Notch activation rescues arterial marker expression. Our work suggests that Akt activity is critical for early artery development, in part via FOXO and Notch-mediated regulation.

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Section: Discussionmentioning

confidence: 99%

Akt is required for artery formation during embryonic vascular development

Zhou

Ristori

et al. 2020

Preprint

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“…SRc-dependent phosphorylation of NIcd1 within the intracellular ankyrin repeat region represses Notch signaling through blockade of the NIcd1-MAML interaction and degradation of NIcd1 (27). AKT-dependent phosphorylation of NIcd4 at S1495, S1847, S1865 and S1917 tethers NIcd4 in the cytoplasm and represses NIcd4-dependent transcription (28). MdM2-dependent NIcd4 ubiquitination and E3 ubiquitin-protein ligase LNX (NUMB)-dependent NIcd1 ubiquitination degrade NIcds and attenuate Notch signaling (29,30), whereas MdM2-dependent NIcd1 ubiquitination does not degrade NIcd1 and activates Notch signaling (31).…”

Section: Notch Signaling Overviewmentioning

confidence: 99%

Precision medicine for human cancers with Notch signaling dysregulation (Review)

Katoh¹,

2019

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NOTcH1, NOTcH2, NOTcH3 and NOTcH4 are transmembrane receptors that transduce juxtacrine signals of the delta-like canonical Notch ligand (dLL)1, dLL3, dLL4, jagged canonical Notch ligand (JAG)1 and JAG2. canonical Notch signaling activates the transcription of BMI1 proto-oncogene polycomb ring finger, cyclin D1, CD44, cyclin dependent kinase inhibitor 1A, hes family bHLH transcription factor 1, hes related family bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing transcription factor and transcription factor 7 in a cellular context-dependent manner, while non-canonical Notch signaling activates NF-κB and Rac family small GTPase 1. Notch signaling is aberrantly activated in breast cancer, non-small-cell lung cancer and hematological malignancies, such as T-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, Notch signaling is inactivated in small-cell lung cancer and squamous cell carcinomas. Loss-of-function NOTCH1 mutations are early events during esophageal tumorigenesis, whereas gain-of-function NOTCH1 mutations are late events during T-cell leukemogenesis and B-cell lymphomagenesis. Notch signaling cascades crosstalk with fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor-suppressive effects in a cancer stage-or (sub)type-dependent manner. Small-molecule γ-secretase inhibitors (AL101, MRK-560, nirogacestat and others) and antibody-based biologics targeting Notch ligands or receptors [ABT-165, AMG 119, rovalpituzumab tesirine (Rova-T) and others] have been developed as investigational drugs. The dLL3-targeting antibody-drug conjugate (Adc) Rova-T, and dLL3-targeting chimeric antigen receptor-modified T cells (CAR-Ts), AMG 119, are promising anti-cancer therapeutics, as are other Adcs or cARTs targeting tumor necrosis factor receptor superfamily member 17, cd19, cd22, cd30, cd79B, cd205, claudin 18.2, fibroblast growth factor receptor (FGFR)2, FGFR3, receptor-type tyrosine-protein kinase FLT3, HER2, hepatocyte growth factor receptor, NEcTIN4, inactive tyrosine-protein kinase 7, inactive tyrosine-protein kinase transmembrane receptor ROR1 and tumor-associated calcium signal transducer 2. Adcs and cARTs could alter the therapeutic framework for refractory cancers, especially diffuse-type gastric cancer, ovarian cancer and pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova-T for patients with small-cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch-related knowledge-base and optimize Notch-targeted therapy for patients with cancer.

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“…expression and transcriptional activity (Espinosa et al, 2003;Liu et al, 2003;McKenzie et al, 2006;Dail et al, 2014;Ramakrishnan et al, 2015). Additionally, this group showed that PI3K inhibition resulted in NOTCH1 protein downregulation in T-ALL cells (Calzavara et al, 2008).…”

Section: Discussionmentioning

confidence: 98%

“…The regulative activity of PI3K/AKT on NOTCH signaling is far less studied. Recent evidence indicates that the PI3K/AKT pathway positively controls NOTCH receptors by regulating their gene expression and transcriptional activity (Espinosa et al, ; Liu et al, ; McKenzie et al, ; Dail et al, ; Ramakrishnan et al, ). Additionally, this group showed that PI3K inhibition resulted in NOTCH1 protein downregulation in T‐ALL cells (Calzavara et al, ).…”

Section: Discussionmentioning

confidence: 99%

PI3K/AKT signaling inhibits NOTCH1 lysosome‐mediated degradation

Platonova

Manzo

Mirandola

et al. 2015

Genes Chromosomes & Cancer

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The pathways of NOTCH and PI3K/AKT are dysregulated in about 60% and 48% of T-cell acute lymphoblastic leukemia (T-ALL) patients, respectively. In this context, they interact and cooperate in controlling tumor cell biology. Here, we propose a novel mechanism by which the PI3K/AKT pathway regulates NOTCH1 in T-ALL, starting from the evidence that the inhibition of PI3K/AKT signaling induced by treatment with LY294002 or transient transfection with a dominant negative AKT mutant downregulates NOTCH1 protein levels and activity, without affecting NOTCH1 transcription. We showed that the withdrawal of PI3K/AKT signaling was associated to NOTCH1 phosphorylation in tyrosine residues and monoubiquitination of NOTCH1 detected by Ubiquitin capture assay. Co-immunoprecipitation assay and colocalization analysis further showed that the E3 ubiquitin ligase c-Cbl interacts and monoubiquitinates NOTCH1, activating its lysosomal degradation. These results suggest that the degradation of NOTCH1 could represent a mechanism of control by which NOTCH1 receptors are actively removed from the cell surface. This mechanism is finely regulated by the PI3K/AKT pathway in physiological conditions. In pathological conditions characterized by PI3K/AKT hyperactivation, such as T-ALL, the excessive AKT signaling could lead to NOTCH1 signaling dysregulation. Therefore, a therapeutic strategy directed to PI3K/AKT in T-ALL could contemporaneously inhibit the dysregulated NOTCH1 signaling. © 2015 Wiley Periodicals, Inc.

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AKT and 14-3-3 Regulate Notch4 Nuclear Localization

Cited by 24 publications

References 38 publications

Akt is required for artery formation during embryonic vascular development

Akt is required for artery formation during embryonic vascular development

Precision medicine for human cancers with Notch signaling dysregulation (Review)

PI3K/AKT signaling inhibits NOTCH1 lysosome‐mediated degradation

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