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Bergo A1, Strollo M1, Gai M2, Barbiero I1, Stefanelli G1, Sertic S3, Cobolli Gigli C4, Di Cunto F2, Kilstrup-Nielsen C1, Landsberger N5. J Biol Chem. 2015;290(6):3223-37.
[expand title=”Show Affiliations”]1From the Department of Theoretical and Applied Sciences, Section of Biomedical Research, University of Insubria, 21052 Busto Arsizio, Italy.
2the Molecular Biotechnology Center, Department of Molecular Biotechnologies and Health Sciences, University of Turin, 10126 Turin, Italy.
3the Department of Life Sciences, University of Milan, 20133 Milan, Italy, and.
4the San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.
5From the Department of Theoretical and Applied Sciences, Section of Biomedical Research, University of Insubria, 21052 Busto Arsizio, Italy, the San Raffaele Rett Research Unit, Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy [email protected].
[/expand]Abstract
Mutations in Methyl-CpG binding protein 2 cause a broad spectrum of neuropsychiatric disorders of which Rett syndrome represents the best defined condition. Both neuronal and non-neuronal functions of the methyl-binding protein underlie the related pathologies. Nowadays Methyl-CpG binding protein 2 is recognized as a multifunctional protein that modulates its activity depending on its protein partners and posttranslational modifications. However, we are still missing a comprehensive understanding of all Methyl-CpG binding protein 2 functions and their involvement in the related pathologies. The study of human mutations often offers the possibility of clarifying the functions of a protein. Therefore, we decided to characterize a novel Methyl-CpG binding protein 2 phospho-isoform (Tyr-120) whose relevance was suggested by a Rett syndrome patient carrying a Y120D substitution possibly mimicking a constitutively phosphorylated state. Unexpectedly, we found Methyl-CpG binding protein 2 and its Tyr-120 phospho – isoform enriched at the centrosome both in dividing and postmitotic cells. The molecular and functional connection of Methyl-CpG binding protein 2 to the centrosome was further reinforced through cellular and biochemical approaches. We show that, similar to many centrosomal proteins, MeCP2 deficiency causes aberrant spindle geometry, prolonged mitosis, and defects in microtubule nucleation. Collectively, our data indicate a novel function of Methyl-CpG binding protein 2 that might reconcile previous data regarding the role of Methyl-CpG binding protein 2 in cell growth and cytoskeleton stability and that might be relevant to understand some aspects of Methyl-CpG binding protein 2 -related conditions. Furthermore, they link the Tyr-120 residue and its phosphorylation to cell division, prompting future studies on the relevance of Tyr-120 for cortical development.
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Go To J. Biol. Chem.Figure legend:
Spindle pole geometry is altered in HeLa and MRC5 cells silenced for Methyl-CpG binding protein 2 expression through specific siRNAs. Cells were stained with antibodies against a-tubulin (red) and g-tubulin (green) or with DAPI (blue). Whereas control cells have bipolar spindles and precisely aligned DNA along the metaphasic midplane, Methyl-CpG binding protein 2-deficient cells are characterized by mono- or multipolar spindles and mis-aligned DNA.
