Publicaties
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A key function for the PP1 interactor NIPP1 in cancer cell proliferation and gene expression KU Leuven
Polycomb Group (PcG) proteins are repressive chromatin modifiers that are important in maintaining stem cell pluripotency, establishing cell fate and cancer development. One of the key events in PcG-mediated gene silencing is the trimethylation of Lysine 27 on histone H3 (H3K27) by the methyltransferase EZH2, a core component of the Polycomb Repressive Complex 2 (PRC2) complex. NIPP1, an interactor of protein Ser/Thr phosphatase PP1, is a ...
Structure of NPP1, an Ectonucleotide Pyrophosphatase/Phosphodiesterase Involved in Tissue Calcification KU Leuven
Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) converts extracellular nucleotides into inorganic pyrophosphate, whereas its close relative NPP2/autotaxin hydrolyzes lysophospholipids. NPP1 regulates calcification in mineralization-competent tissues, and a lack of NPP1 function underlies calcification disorders. Here, we show that NPP1 forms homodimers via intramembrane disulfide bonding, but is also processed intracellularly to a ...
Kinetic analysis of substrate utilization by native and TNAP-, NPP1- or PHOSPHO1-deficient matrix vesicles KU Leuven
During the process of endochondral bone formation, chondrocytes and osteoblasts mineralize their extracellular matrix by promoting the formation of hydroxyapatite seed crystals in the sheltered interior of membrane-limited matrix vesicles (MVs). Here, we have studied phosphosubstrate catalysis by osteoblast-derived MVs at physiologic pH, analyzing the hydrolysis of ATP, ADP, and PP(i) by isolated wild-type (WT) as well as TNAP-, NPP1- and ...
NIPP1 maintains EZH2 phosphorylation and promoter occupancy KU Leuven
Polycomb Group (PcG) proteins are repressive chromatin modifiers that regulate stem-cell pluripotency and differentiation, and are involved in cancer development. They function in large multimeric protein collections termed Polycomb Repressive complexes (PRC) and a key step in PcG-mediated gene silencing is the trimethylation of histone H3 at lysine 27 (H3K27me3) by the PRC2-component EZH2. Both the chromatin targeting of EZH2 and its affinity ...
Een sleutelrol voor NIPP1 in lever stamcel proliferatie en alkylatie-geïntroduceerde leverkanker KU Leuven
Summary The multifunctional scaffold protein NIPP1 interacts with the Ser/Thr phosphatase PP1, but also contains a substrate-interacting domain that binds, amongst others, several ligands when phosphorylated on specific residues, such as protein kinase MELK. Since NIPP1-/- mice proved to be embryonic lethal at the onset of gastrulation, the main goal of my thesis was to further characterize the function of NIPP1 in vivo. This was done by ...
NIPP1 maintains EZH2 phosphorylation and promoter occupancy at proliferation-related target genes KU Leuven
The histone methyltransferase EZH2 regulates cell proliferation and differentiation by silencing Polycomb group target genes. NIPP1, a nuclear regulator of serine/threonine protein phosphatase 1 (PP1), has been implicated in the regulation of EZH2 occupancy at target loci, but the underlying mechanism is not understood. Here, we demonstrate that the phosphorylation of EZH2 by cyclin-dependent kinases at Thr416 creates a docking site for the ...
The phosphatase interactor NIPP1 regulates the occupancy of the histone methyltransferase EZH2 at Polycomb targets KU Leuven
Polycomb group (PcG) proteins are key regulators of stem-cell and cancer biology. They mainly act as repressors of differentiation and tumor-suppressor genes. One key silencing step involves the trimethylation of histone H3 on Lys27 (H3K27) by EZH2, a core component of the Polycomb Repressive Complex 2 (PRC2). The mechanism underlying the initial recruitment of mammalian PRC2 complexes is not well understood. Here, we show that NIPP1, a ...
DNA damage-induced allosteric activation of protein phosphatase PP1:NIPP1 through Src kinase-induced circularization of NIPP1 KU Leuven
Protein phosphatase-1 (PP1) complexed to nuclear inhibitor of PP1 (NIPP1) limits DNA repair through dephosphorylation of NIPP1-recruited substrates. However, the PP1:NIPP1 holoenzyme is completely inactive under basal conditions, hinting at a DNA damage-regulated activation mechanism. Here, we report that DNA damage caused the activation of PP1:NIPP1 after a time delay of several hours through phosphorylation of NIPP1 at the C-terminal tyrosine ...