title: MAPK-dependent phosphorylation modulates the activity of Suppressor of Hairless in Drosophila.
abstract: Cell differentiation strictly depends on the epidermal growth factor receptor (EGFR)- and Notch-signalling pathways, which are closely intertwined. Here we address the molecular cross talk at the level of Suppressor of Hairless [Su(H)]. The Drosophila transcription factor Su(H) mediates Notch signalling at the DNA level: in the presence of signalling input Su(H) assembles an activator complex on Notch target genes and a repressor complex in its absence. Su(H) contains a highly conserved mitogen activated protein kinase (MAPK) target sequence. Here we provide evidence that Su(H) is phosphorylated in response to MAPK activity. Mutation of the Su(H) MAPK-site modulated the Notch signalling output: whereas a phospho-deficient Su(H)(MAPK-ko) isoform provoked a stronger Notch signalling activity, a phospho-mimetic Su(H)(MAPK-ac) mutant resulted in its attenuation. In vivo assays in Drosophila cell culture as well as in flies support the idea that Su(H) phosphorylation affects the dynamics of repressor or activator complex formation or the transition from the one into the other complex. In summary, the phosphorylation of Su(H) attenuates Notch signalling in vivo in several developmental settings. Consequently, a decrease of EGFR signal causes an increase of Notch signalling intensity. Hence, the antagonistic relationship between EGFR- and Notch-signalling pathways may involve a direct modification of Su(H) by MAPK in several developmental contexts of fly development. The high sequence conservation of the MAPK target site in the mammalian Su(H) homologues supports the idea that EGFR signalling impacts on Notch activity in a similar way in humans as well.
authors.affiliation: Institut für Genetik (240A), Universität Hohenheim, Garbenstr. 30 Stuttgart, 70599, Germany.
authors.forename: Jasmin S
authors.initials: JS
authors.lastname: Auer
authors.affiliation: Institut für Genetik (240A), Universität Hohenheim, Garbenstr. 30 Stuttgart, 70599, Germany.
authors.forename: Anja C
authors.initials: AC
authors.lastname: Nagel
authors.affiliation: Institut für Genetik (240A), Universität Hohenheim, Garbenstr. 30 Stuttgart, 70599, Germany.
authors.forename: Adriana
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Institut für Genetik (240A), Universität Hohenheim, Garbenstr. 30 Stuttgart, 70599, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Wahl
authors.affiliation: Institut für Genetik (240A), Universität Hohenheim, Garbenstr. 30 Stuttgart, 70599, Germany. Electronic address: a.preiss@uni-hohenheim.de.
authors.forename: Anette
authors.initials: A
authors.lastname: Preiss
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D017930:Genes, Reporter; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D020239:Receptor Cross-Talk; D051880:Receptors, Notch / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014921:Wings, Animal / Q000254:growth & development / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D010750:Phosphoproteins; D051880:Receptors, Notch; D012097:Repressor Proteins; C088731:Su(H) protein, Drosophila; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases
keywords: Drosophila; EGFR signalling; MAPK; Notch signalling; Su(H)