Methyl-CpG-binding protein 2 is phosphorylated by homeodomain-interacting protein kinase 2 and contributes to apoptosis.
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.
Bracaglia
Giorgia
G
Department of Experimental Oncology, Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Rome 00158, Italy.
Conca
Barbara
B
Bergo
Anna
A
Rusconi
Laura
L
Zhou
Zhaolan
Z
Greenberg
Michael E
ME
Landsberger
Nicoletta
N
Soddu
Silvia
S
Kilstrup-Nielsen
Charlotte
C
D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004622:Embryo, Mammalian; D006367:HeLa Cells; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012694:Serine / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; D051783:Methyl-CpG-Binding Protein 2; D050505:Mutant Proteins; D034741:RNA, Small Interfering; D012694:Serine; D004247:DNA; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases