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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 Ser 269  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 [ Su(H)  S 269 A   ] or a phospho-mimetic [ Su(H)  S 269 D   ] isoform.  Su(H)  S 269 D    mutants were defective of Notch activity in all analyzed tissues, consistent with impaired DNA-binding. In contrast, the phospho-deficient  Su(H)  S 269 A    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  S 221 D   was dysfunctional in both the fly as well as two human cell culture models, whereas phospho-deficient RBPJ  S 221 A   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.

Phospho-Site Mutations in Transcription Factor Suppressor of Hairless Impact Notch Signaling Activity During Hematopoiesis in Drosophila