The Conserved MAPK Site in E(spl)-M8, an Effector of Drosophila Notch Signaling, Controls Repressor Activity during Eye Development
| Autor: | Ashok P. Bidwai, Mohna Bandyopadhyay, Clifton P. Bishop |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Photoreceptors
0301 basic medicine MAPK/ERK pathway Cell signaling Sensory Receptors Organogenesis Social Sciences lcsh:Medicine Signal transduction Eye Biochemistry Inhibitions Animal Cells Basic Helix-Loop-Helix Transcription Factors Medicine and Health Sciences Drosophila Proteins Psychology Protein Phosphatase 2 Phosphorylation Post-Translational Modification Casein Kinase II lcsh:Science Conserved Sequence Neurons Notch Signaling Genetics Multidisciplinary Receptors Notch Effector Kinase Drosophila Melanogaster 05 social sciences Gene Expression Regulation Developmental Signaling cascades Animal Models Cell biology ErbB Receptors Insects Photoreceptor Cells Invertebrate Sensory Perception Drosophila Mitogen-Activated Protein Kinases Anatomy Cellular Types EGFR signaling Research Article 050104 developmental & child psychology MAPK signaling cascades Arthropoda Repressor Nerve Tissue Proteins Biology Research and Analysis Methods 03 medical and health sciences Model Organisms Ocular System Animals 0501 psychology and cognitive sciences Amino Acid Sequence Receptors Invertebrate Peptide Enhancer Psychological repression Behavior lcsh:R Organisms Biology and Life Sciences Afferent Neurons Proteins Protein phosphatase 2 Invertebrates Repressor Proteins 030104 developmental biology Cellular Neuroscience Mutation Eyes lcsh:Q Sequence Alignment Head Neuroscience |
| Zdroj: | PLoS ONE, Vol 11, Iss 7, p e0159508 (2016) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | The specification of patterned R8 photoreceptors at the onset of eye development depends on timely inhibition of Atonal (Ato) by the Enhancer of split (E(spl) repressors. Repression of Ato by E(spl)-M8 requires the kinase CK2 and is inhibited by the phosphatase PP2A. The region targeted by CK2 harbors additional conserved Ser residues, raising the prospect of regulation via multi-site phosphorylation. Here we investigate one such motif that meets the consensus for modification by MAPK, a well-known effector of Epidermal Growth Factor Receptor (EGFR) signaling. Our studies reveal an important role for the predicted MAPK site of M8 during R8 birth. Ala/Asp mutations reveal that the CK2 and MAPK sites ensure that M8 repression of Ato and the R8 fate occurs in a timely manner and at a specific stage (stage-2/3) of the morphogenetic furrow (MF). M8 repression of Ato is mitigated by halved EGFR dosage, and this effect requires an intact MAPK site. Accordingly, variants with a phosphomimetic Asp at the MAPK site exhibit earlier (inappropriate) activity against Ato even at stage-1 of the MF, where a positive feedback-loop is necessary to raise Ato levels to a threshold sufficient for the R8 fate. Analysis of deletion variants reveals that both kinase sites (CK2 and MAPK) contribute to ‘cis’-inhibition of M8. This key regulation by CK2 and MAPK is bypassed by the E(spl)D mutation encoding the truncated protein M8*, which potently inhibits Ato at stage-1 of R8 birth. We also provide evidence that PP2A likely targets the MAPK site. Thus multi-site phosphorylation controls timely onset of M8 repressor activity in the eye, a regulation that appears to be dispensable in the bristle. The high conservation of the CK2 and MAPK sites in the insect E(spl) proteins M7, M5 and Mγ, and their mammalian homologue HES6, suggest that this mode of regulation may enable E(spl)/HES proteins to orchestrate repression by distinct tissue-specific mechanisms, and is likely to have broader applicability than has been previously recognized. |
| Databáze: | OpenAIRE |
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