Journal Article

Methyl-CpG-binding protein 2 is phosphorylated by homeodomain-interacting protein kinase 2 and contributes to apoptosis

Landsberger, Nicoletta, Kilstrup‐Nielsen, Charlotte, Soddu, Silvia, Rusconi, Laura, Greenberg, Michael E, Bergo, Anna, Zhou, Zhaolan, Conca, Barbara, Bracaglia, Giorgia

2009

Overview

Mutations in the methyl‐CpG‐binding protein 2 (MeCP2) are associated with Rett syndrome and other neurological disorders. MeCP2 represses transcription mainly by recruiting various co‐repressor complexes. Recently, MeCP2 phosphorylation at Ser 80, Ser 229 and Ser 421 was shown to occur in the brain and modulate MeCP2 silencing activities. However, the kinases directly responsible for this are largely unknown. Here, we identify the homeodomain‐interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo . HIPK2 modulates cell proliferation and apoptosis, and the neurological defects of Hipk2 ‐null mice indicate its role in proper brain functions. We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. These data are, to our knowledge, the first that describe a kinase associating with MeCP2, causing its specific phosphorylation in vivo and, furthermore, they reinforce the role of MeCP2 in regulating cell growth. Rett syndrome is a severe neurological disorder caused by mutations in the gene MECP2. Bracaglia and colleagues now identify the kinase HIPK2 as capable of specifically phosphorylating MeCP2 protein at Serine 80 in vivo. They show that MeCP2 cooperates with HIPK2 to induce apoptosis, providing insight into the function of this disease‐associated protein.

• Publisher: John Wiley & Sons, Ltd,Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: Amino Acid Substitution - physiology / Animals / Apoptosis / Apoptosis - drug effects / Apoptosis - genetics / Carrier Proteins - antagonists & inhibitors / Carrier Proteins - metabolism / Cells, Cultured / Deoxyribonucleic acid / DNA / DNA - metabolism / EMBO31 / Embryo, Mammalian / HeLa Cells / HIPK2 / Humans / MeCP2 / Methyl-CpG-Binding Protein 2 - genetics / Methyl-CpG-Binding Protein 2 - metabolism / Methyl-CpG-Binding Protein 2 - physiology / Mice / Mutant Proteins - genetics / Mutant Proteins - metabolism / Mutation / Neurological disorders / NIH 3T3 Cells / phosphorylation / Phosphorylation - drug effects / Phosphorylation - genetics / Protein Binding - drug effects / Protein Binding - genetics / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein Serine-Threonine Kinases - metabolism / Proteins / RNA, Small Interfering - pharmacology / Scientific Report / Serine - genetics / Serine - metabolism