Nuclear PtdIns5P as a transducer of stress signaling: an in vivo role for PIP4Kbeta.
Inhibitor of growth protein-2 (ING2) is a nuclear adaptor protein that can regulate p53 and histone acetylation in response to cellular stress and contains a PHD (plant homeodomain) finger that can interact with phosphatidylinositol-5-phosphate (PtdIns5P). However, whether or how nuclear PtdIns5P levels are regulated in response to cellular stress or whether ING2 can sense these changes has not been demonstrated. We show that UV irradiation increases nuclear PtdIns5P levels via inhibition of the activity of the beta isoform of PtdIns5P 4-kinase (PIP4Kbeta), an enzyme that can phosphorylate and remove PtdIns5P. Inhibition of PIP4Kbeta activity occurs through the direct phosphorylation of PIP4Kbeta at Ser326 by the p38 stress-activated protein kinase. Finally, we show that changes in nuclear PtdIns5P are translated into changes in the association of ING2 with chromatin. Our data define a pathway connecting cellular stressors with changes in nuclear PtdIns5P levels and the regulation of PHD motif-containing proteins.
Jones
David R
DR
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
Bultsma
Yvette
Y
Keune
Willem-Jan
WJ
Halstead
Jonathan R
JR
Elouarrat
Dallila
D
Mohammed
Shabaz
S
Heck
Albert J
AJ
D'Santos
Clive S
CS
Divecha
Nullin
N
D019870:1-Phosphatidylinositol 4-Kinase / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000528:radiation effects; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D010768:Phosphoserine / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018398:Homeodomain Proteins; C512177:ING2 protein, mouse; D018129:Phosphatidylinositol Phosphates; D025521:Tumor Suppressor Proteins; C113567:phosphatidylinositol 5-phosphate; D010768:Phosphoserine; D019870:1-Phosphatidylinositol 4-Kinase; D048051:p38 Mitogen-Activated Protein Kinases