Phosphorylation of serine 239 of Groucho/TLE1 by protein kinase CK2 is important for inhibition of neuronal differentiation.
Transcriptional corepressors of the Groucho (Gro)/TLE family play important roles during a variety of developmental pathways, including neuronal differentiation. In particular, they act as negative regulators of neurogenesis, together with Hairy/Enhancer of split (Hes) DNA-binding proteins. The interaction with Hes1 leads to Gro/TLE hyperphosphorylation and increased transcription repression activity in mammalian cells, but the underlying molecular mechanisms are poorly characterized. We now show that Gro/TLE1 is phosphorylated in vivo by protein kinase CK2. This phosphorylation occurs at serine 239 within the conserved CcN domain present in all Gro/TLE family members. Mutation of serine 239 into alanine decreases Hes1-induced hyperphosphorylation of Gro/TLE1 and also reduces its nuclear association and transcription repression activity. We demonstrate further that Gro/TLE1 inhibits the transition of cortical neural progenitors into neurons and that its antineurogenic activity is inhibited by a serine-239-alanine mutation but not by a serine-239-glutamate mutation. These results suggest that CK2 phosphorylation of serine 239 of Gro/TLE1 is important for its function during neuronal differentiation.
Nuthall
Hugh N
HN
Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
Joachim
Kerline
K
Stifani
Stefano
S
D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D047390:Casein Kinase II; D002454:Cell Differentiation / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D047390:Casein Kinase II; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D017346:Protein Serine-Threonine Kinases; D012097:Repressor Proteins; D012694:Serine; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C499043:TLE1 protein, human; C434946:Tle1 protein, mouse; C091023:gro protein, Drosophila; C078493:HES1 protein, human