Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

Broadus, Matthew R.; Chen, Tony W.; Neitzel, Leif R.; Ng, Victoria; Jodoin, Jeanne N.; Lee, Laura A.; Robbins, David J.; Capobianco, Anthony J.; Patton, James G.; Huppert, Stacey S.; Lee, Ethan

doi:10.1016/j.celrep.2016.04.070

Cited by 9 publications

(12 citation statements)

References 31 publications

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“…The carcinogenicity of NICD has been demonstrated in various cancers such as lung, blood, head and neck, brain, and breast cancer (Mukherjee et al, 2016;Yeh et al, 2016;Yu et al, 2016). The roles of Plac1 in the progression of cancers have been directly ascribed to its processing activity that gives rise to the activation of cancer-related signal pathway proteins-Notch1 pathway (Broadus et al, 2016;Tao et al, 2014). By gain-and loss-of-function assays, we show that depletion of Furin in Plac1-overexpressing breast cancer cells attenuated the Plac1induced expression of NICD, HES1, MMP2, and MMP9 and tumor cell invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Cancer/testis antigen‐Plac1 promotes invasion and metastasis of breast cancer through Furin/NICD/PTEN signaling pathway

Chu

et al. 2018

Molecular Oncology

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Placenta‐specific protein 1 (Plac1) is a cancer/testis antigen that plays a critical role in promoting cancer initiation and progression. However, the clinical significance and mechanism of Plac1 in cancer progression remain elusive. Here, we report that Plac1 is an important oncogenic and prognostic factor, which physically interacts with Furin to drive breast cancer invasion and metastasis. We have shown that Plac1 expression positively correlates with clinical stage, lymph node metastasis, hormone receptor status, and overall patient survival. Overexpression of Plac1 promoted invasion and metastasis of breast cancer cells in vitro and in vivo. Co‐immunoprecipitation and immunofluorescence cell staining assays revealed that interaction of Plac1 and Furin degraded Notch1 and generated Notch1 intracellular domain (NICD) that could inhibit PTEN activity. These findings are consistent with the results of microarray study in MDA‐MB‐231 cells overexpressing Plac1. A rescue study showed that inhibition of Furin and overexpression of PTEN in Plac1 overexpression cells blocked Plac1‐induced tumor cell progression. Taken together, our findings suggest that functional interaction between Plac1 and Furin enhances breast cancer invasion and metastasis and the Furin/NICD/PTEN axis may act as an important therapeutic target for breast cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Cancer/testis antigen‐Plac1 promotes invasion and metastasis of breast cancer through Furin/NICD/PTEN signaling pathway

Chu

et al. 2018

Molecular Oncology

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“…Notch ICD degradation may also be controlled by CSL. Recently, a novel degradation domain in Notch 1 (the N1-box) was found, which mediates degradation of Notch 1 ICD, but which is blocked by CSL, and the Notch ICD-CSL interaction may thus regulate Notch ICD longevity (76).…”

Section: Posttranslational Modifications Of Notch Icdmentioning

confidence: 99%

Notch Signaling in Development, Tissue Homeostasis, and Disease

Siebel

Lendahl

2017

Physiological Reviews

772

677

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Notch signaling is an evolutionarily highly conserved signaling mechanism, but in contrast to signaling pathways such as Wnt, Sonic Hedgehog, and BMP/TGF-β, Notch signaling occurs via cell-cell communication, where transmembrane ligands on one cell activate transmembrane receptors on a juxtaposed cell. Originally discovered through mutations in more than 100 yr ago, and with the first Notch gene cloned more than 30 yr ago, we are still gaining new insights into the broad effects of Notch signaling in organisms across the metazoan spectrum and its requirement for normal development of most organs in the body. In this review, we provide an overview of the Notch signaling mechanism at the molecular level and discuss how the pathway, which is architecturally quite simple, is able to engage in the control of cell fates in a broad variety of cell types. We discuss the current understanding of how Notch signaling can become derailed, either by direct mutations or by aberrant regulation, and the expanding spectrum of diseases and cancers that is a consequence of Notch dysregulation. Finally, we explore the emerging field of Notch in the control of tissue homeostasis, with examples from skin, liver, lung, intestine, and the vasculature.

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“…A number of these phospho-degrons have been identified in the NICD PEST domain. Intriguingly, an additional hNICD1-specific degron has recently been identified within the N-terminal region, distinct from the PEST domain that is not recognized by FBXW7 (Broadus et al, 2016). Moreover, the E3 ligase, Itch, promoting PEST domain-independent NICD1 degradation (Qiu et al, 2000), does not mediate NICD1 degradation through the N1-Box (Broadus et al, 2016).…”

Section: Fbxw7 and Its Role In Nicd Turnovermentioning

confidence: 99%

Turn It Down a Notch

Carrieri

Dale

2017

Front. Cell Dev. Biol.

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In the developing vertebrate embryo, segmentation initiates through the formation of repeated segments, or somites, on either side of the posterior neural tube along the anterior to posterior axis. The periodicity of somitogenesis is regulated by a molecular oscillator, the segmentation clock, driving cyclic gene expression in the unsegmented paraxial mesoderm, from which somites derive. Three signaling pathways underlie the molecular mechanism of the oscillator: Wnt, FGF, and Notch. In particular, Notch has been demonstrated to be an essential piece in the intricate somitogenesis regulation puzzle. Notch is required to synchronize oscillations between neighboring cells, and is moreover necessary for somite formation and clock gene oscillations. Following ligand activation, the Notch receptor is cleaved to liberate the active intracellular domain (NICD) and during somitogenesis NICD itself is produced and degraded in a cyclical manner, requiring tightly regulated, and coordinated turnover. It was recently shown that the pace of the segmentation clock is exquisitely sensitive to levels/stability of NICD. In this review, we focus on what is known about the mechanisms regulating NICD turnover, crucial to the activity of the pathway in all developmental contexts. To date, the regulation of NICD stability has been attributed to phosphorylation of the PEST domain which serves to recruit the SCF/Sel10/FBXW7 E3 ubiquitin ligase complex involved in NICD turnover. We will describe the pathophysiological relevance of NICD-FBXW7 interaction, whose defects have been linked to leukemia and a variety of solid cancers.

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Identification of a Paralog-Specific Notch1 Intracellular Domain Degron

Cited by 9 publications

References 31 publications

Cancer/testis antigen‐Plac1 promotes invasion and metastasis of breast cancer through Furin/NICD/PTEN signaling pathway

Cancer/testis antigen‐Plac1 promotes invasion and metastasis of breast cancer through Furin/NICD/PTEN signaling pathway

Notch Signaling in Development, Tissue Homeostasis, and Disease

Turn It Down a Notch

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