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Molecular and Cellular Biology, October 2004, p. 8395-8407, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8395-8407.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Phosphorylation of Serine 239 of Groucho/TLE1 by Protein Kinase CK2 Is Important for Inhibition of Neuronal Differentiation

Hugh N. Nuthall, Kerline Joachim, and Stefano Stifani*

Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada

Received 5 April 2004/ Returned for modification 12 May 2004/ Accepted 30 June 2004

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.

* Corresponding author. Mailing address: Center for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada. Phone: (514) 398-3946. Fax: (514) 398-1319. E-mail: stefano.stifani{at}mcgill.ca.

Molecular and Cellular Biology, October 2004, p. 8395-8407, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8395-8407.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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