The lysine-specific demethylase 1 is a novel substrate of protein kinase CK2.
Protein kinase CK2 is a pleiotropic serine/threonine kinase responsible for the generation of a substantial proportion of the human phosphoproteome. CK2 is generally found as a tetramer with two catalytic, α and α' and two non catalytic β subunits. CK2α C-terminal tail phosphorylation is regulated during the mitotic events and the absence of these phosphosites in α' suggests an isoform specialization. We used a proteomic approach to identify proteins specifically phosphorylated by a CK2α phosphomimetic mutant, CK2αT344ET360ES362ES370E (CK2α4E), in human neuroblastoma SKNBE cellular extract. One of these proteins is lysine-specific demethylase 1 (LSD1 or KDM1A), an important player of the epigenetic machinery. LSD1 is a FAD-dependent amine oxidase and promotes demethylation of lysine 4 and lysine 9 of mono- and di-methylated histone H3. We found that LSD1 is a new substrate and an interacting partner of protein kinase CK2. Three CK2 phosphosites, (Ser131, Ser137 and Ser166) in the N-terminal region of LSD1 have been identified. This domain is found in all chordates but not in more ancient organisms and it is not essential for LSD1 catalytic event while it could modulate the interaction with CK2 and with other partners in gene repressing and activating complexes. Our data support the view that the phosphorylation of the N-terminal domain by CK2 may represent a mechanism for regulating histone methylation, disclosing a new role for protein kinase CK2 in epigenetics.
Department of Biomedical Sciences and CNR Institute of Neurosciences, Viale G. Colombo, University of Padova, 35131 Padova, Italy.
Roberto
R
Costa
Department of Biomedical Sciences and CNR Institute of Neurosciences, Viale G. Colombo, University of Padova, 35131 Padova, Italy; Proteomic Center of Padova University, Via G. Orus 2b, 35129 Padova, Italy.
Giorgio
G
Arrigoni
Department of Biomedical Sciences and CNR Institute of Neurosciences, Viale G. Colombo, University of Padova, 35131 Padova, Italy.
Giorgio
G
Cozza
Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
Graziano
G
Lolli
Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
Roberto
R
Battistutta
Center for Regenerative Medicine in Barcelona, Dr. Aiguader 88, 08003 Barcelona, Spain; Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Juan Carlos
JC
Izpisua Belmonte
Department of Biomedical Sciences and CNR Institute of Neurosciences, Viale G. Colombo, University of Padova, 35131 Padova, Italy.
Lorenzo A
LA
Pinna
Department of Biomedical Sciences and CNR Institute of Neurosciences, Viale G. Colombo, University of Padova, 35131 Padova, Italy. Electronic address: stefania.sarno@unipd.it.
Stefania
S
Sarno
D000595:Amino Acid Sequence; D000818:Animals; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D006657:Histones; D021122:Protein Subunits; D011994:Recombinant Proteins; D012694:Serine; D056466:Histone Demethylases; C495195:KDM1A protein, human; D047390:Casein Kinase II; D008239:Lysine
CK2; Demethylation; Epigenetics; LSD1; Phosphorylation