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Frankenreiter, L., Gahr, B.M., Schmid, H., Zimmermann, M., Deichsel, S., Hoffmeister, P., Turkiewicz, A., Borggrefe, T., Oswald, F., Nagel, A.C. (2021). Phospho-Site Mutations in Transcription Factor Suppressor of Hairless Impact Notch Signaling Activity During Hematopoiesis in Drosophila.  Front. Cell Dev. Biol. 9(): 658820.
FlyBase ID
FBrf0248830
Publication Type
Research paper
Abstract

The highly conserved Notch signaling pathway controls a multitude of developmental processes including hematopoiesis. Here, we provide evidence for a novel mechanism of tissue-specific Notch regulation involving phosphorylation of CSL transcription factors within the DNA-binding domain. Earlier we found that a phospho-mimetic mutation of the Drosophila CSL ortholog Suppressor of Hairless Su(H) at Ser269 impedes DNA-binding. By genome-engineering, we now introduced phospho-specific Su(H) mutants at the endogenous Su(H) locus, encoding either a phospho-deficient <up>Su(H) S269A </up> or a phospho-mimetic <up>Su(H) S269D </up> isoform. Su(H) S269D mutants were defective of Notch activity in all analyzed tissues, consistent with impaired DNA-binding. In contrast, the phospho-deficient Su(H) S269A mutant did not generally augment Notch activity, but rather specifically in several aspects of blood cell development. Unexpectedly, this process was independent of the corepressor Hairless acting otherwise as a general Notch antagonist in Drosophila. This finding is in agreement with a novel mode of Notch regulation by posttranslational modification of Su(H) in the context of hematopoiesis. Importantly, our studies of the mammalian CSL ortholog (RBPJ/CBF1) emphasize a potential conservation of this regulatory mechanism: phospho-mimetic RBPJ S221D was dysfunctional in both the fly as well as two human cell culture models, whereas phospho-deficient RBPJ S221A rather gained activity during fly hematopoiesis. Thus, dynamic phosphorylation of CSL-proteins within the DNA-binding domain provides a novel means to fine-tune Notch signal transduction in a context-dependent manner.

PubMed ID
PubMed Central ID
PMC8079769 (PMC) (EuropePMC)
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    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Front. Cell Dev. Biol.
    Title
    Frontiers in cell and developmental biology
    ISBN/ISSN
    2296-634X
    Data From Reference