Turn It Down a Notch

Carrieri, Francesca Anna; Dale, Jacqueline Kim

doi:10.3389/fcell.2016.00151

Cited by 35 publications

(37 citation statements)

References 137 publications

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“…Notch signaling functions in cell fate determination, development, and cancer 47 , 48 . There are four Notch receptors (Notch1–4) in mammals, with Notch1 and 2 most closely related.…”

Section: Resultsmentioning

confidence: 99%

Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation

et al. 2017

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Tankyrase 1 and 2 are poly(ADP-ribose) polymerases that function in pathways critical to cancer cell growth. Tankyrase-mediated PARylation marks protein targets for proteasomal degradation. Here, we generate human knockout cell lines to examine cell function and interrogate the proteome. We show that either tankyrase 1 or 2 is sufficient to maintain telomere length, but both are required to resolve telomere cohesion and maintain mitotic spindle integrity. Quantitative analysis of the proteome of tankyrase double knockout cells using isobaric tandem mass tags reveals targets of degradation, including antagonists of the Wnt/β-catenin signaling pathway (NKD1, NKD2, and HectD1) and three (Notch 1, 2, and 3) of the four Notch receptors. We show that tankyrases are required for Notch2 to exit the plasma membrane and enter the nucleus to activate transcription. Considering that Notch signaling is commonly activated in cancer, tankyrase inhibitors may have therapeutic potential in targeting this pathway.

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“…Notch signaling functions in cell fate determination, development, and cancer 47 , 48 . There are four Notch receptors (Notch1–4) in mammals, with Notch1 and 2 most closely related.…”

Section: Resultsmentioning

confidence: 99%

Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation

et al. 2017

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“…As cells are under the influence of several developmental pathways, molecular cross-talk is required for their coordination 2 , 15 . Indeed, NICD phosphorylation affects complex formation and stability, which eventually results in either stimulation or inhibition of Notch signalling, depending on the mediating kinase and the targeted region of NICD (for review 16 , 17 ). As several of these kinases are also an integral part of other signalling pathways they have the potential to act as the mediators of crosstalk.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of Suppressor of Hairless impedes its DNA-binding activity

Nagel

Auer

Schulz

et al. 2017

Sci Rep

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Notch signalling activity governs cellular differentiation in higher metazoa, where Notch signals are transduced by the transcription factor CSL, called Suppressor of Hairless [Su(H)] in Drosophila. Su(H) operates as molecular switch on Notch target genes: within activator complexes, including intracellular Notch, or within repressor complexes, including the antagonist Hairless. Mass spectrometry identified phosphorylation on Serine 269 in Su(H), potentially serving as a point of cross-regulation by other signalling pathways. To address the biological significance, we generated phospho-deficient [Su(H)S269A] and phospho-mimetic [Su(H)S269D] variants: the latter displayed reduced transcriptional activity despite unaltered protein interactions with co-activators and -repressors. Based on the Su(H) structure, Ser269 phosphorylation may interfere with DNA-binding, which we confirmed by electro-mobility shift assay and isothermal titration calorimetry. Overexpression of Su(H)S269D during fly development demonstrated reduced transcriptional regulatory activity, similar to the previously reported DNA-binding defective mutant Su(H)R266H. As both are able to bind Hairless and Notch proteins, Su(H)S269D and Su(H)R266H provoked dominant negative effects upon overexpression. Our data imply that Ser269 phosphorylation impacts Notch signalling activity by inhibiting DNA-binding of Su(H), potentially affecting both activation and repression. Ser269 is highly conserved in vertebrate CSL homologues, opening the possibility of a general and novel mechanism of modulating Notch signalling activity.

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“…Interestingly, Notch signalling does not require the use of second messengers [4,5] . The activity is exclusively driven by the NICD [6] .…”

Section: Notch Pathwaymentioning

confidence: 99%

Targeting Developmental Pathways: The Achilles Heel of Cancer?

Dempke¹,

Fenchel

Uciechowski

et al. 2017

Oncology

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Developmental pathways (e.g., Notch, Hippo, Hedgehog, Wnt, and TGF-β/BMP/FGF) are networks of genes that act co-ordinately to establish the body plan, and disruptions of genes in one pathway can have effects in related pathways and may result in serious dysmorphogenesis or cancer. Interestingly, all developmental pathways are highly conserved cell signalling systems present in almost all multicellular organisms. In addition, they have a crucial role in cell proliferation, apoptosis, differentiation, and finally in organ development. Of note, almost all of these pathways promote oncogenesis through synergistic associations with the Hippo signalling pathway, and several lines of evidence have also indicated that these pathways (e.g., Wnt/β-catenin) may be implicated in checkpoint inhibitor resistance (e.g., CTLA-4, PD-1, and PD-L1). Since Notch inhibition in vivo results in partial loss of its stemness features such as self-renewal, chemoresistance, invasive and migratory potential, and tumorigenesis, these highly conserved developmental pathways are regarded as being critical for regulation of self-renewal in both embryonic and adult stem cells and hence are likely to be implicated in the maintenance of cancer stem cells. Many small molecules are currently in preclinical and early clinical development, and only two compounds are approved for treatment of advanced or metastatic basal cell carcinoma (vismodegib and sonidegib). Furthermore, therapeutic targeting of cancer stem cells using drugs that disrupt activated developmental pathways may also represent an attractive strategy that is potentially relevant to many types of malignancy, notably blood cancers, where the evidence for leukaemia stem cells is well established. Future work will hopefully pave the way for the development of new strategies for targeting these pervasive oncogenic pathways.

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Turn It Down a Notch

Cited by 35 publications

References 137 publications

Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation

Whole proteome analysis of human tankyrase knockout cells reveals targets of tankyrase-mediated degradation

Phosphorylation of Suppressor of Hairless impedes its DNA-binding activity

Targeting Developmental Pathways: The Achilles Heel of Cancer?

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