Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A.
Notch signalling is used throughout the animal kingdom to spatially and temporally regulate cell fate, proliferation and differentiation. Its importance is reflected in the dramatic effects produced on both development and health by small variations in the strength of the Notch signal. The Down-syndrome-associated kinase DYRK1A is coexpressed with Notch in various tissues during embryonic development. Here we show that DYRK1A moves to the nuclear transcription compartment where it interacts with the intracellular domain of Notch promoting its phosphorylation in the ankyrin domain and reducing its capacity to sustain transcription. DYRK1A attenuates Notch signalling in neural cells both in culture and in vivo, constituting a novel mechanism capable of modulating different developmental processes that can also contribute to the alterations observed during brain development in animal models of Down syndrome.
Fernandez-Martinez
Javier
J
Instituto de Neurociencias, CSIC-UMH, Sant Joan d'Alacant, Alicante, Spain.
Vela
Eva M
EM
Tora-Ponsioen
Mireille
M
Ocaña
Oscar H
OH
Nieto
M Angela
MA
Galceran
Juan
J
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D004314:Down Syndrome / Q000201:enzymology* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D009154:Mutation; D019579:Neocortex / Q000196:embryology / Q000201:enzymology*; D009474:Neurons / Q000201:enzymology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection; D000097603:Dyrk Kinases
D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D051881:Receptor, Notch1; D000097603:Dyrk Kinases; C497762:Notch1 protein, mouse; C066780:Clk dual-specificity kinases