The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor.
Phosphoinositides (PtdInsPs) play critical roles in cytoplasmic signal transduction pathways. However, their functions in the nucleus are unclear, as specific nuclear receptors for PtdInsPs have not been identified. Here, we show that ING2, a candidate tumor suppressor protein, is a nuclear PtdInsP receptor. ING2 contains a plant homeodomain (PHD) finger, a motif common to many chromatin-regulatory proteins. We find that the PHD fingers of ING2 and other diverse nuclear proteins bind in vitro to PtdInsPs, including the rare PtdInsP species, phosphatidylinositol 5-phosphate (PtdIns(5)P). Further, we demonstrate that the ING2 PHD finger interacts with PtdIns(5)P in vivo and provide evidence that this interaction regulates the ability of ING2 to activate p53 and p53-dependent apoptotic pathways. Together, our data identify the PHD finger as a phosphoinositide binding module and a nuclear PtdInsP receptor, and suggest that PHD-phosphoinositide interactions directly regulate nuclear responses to DNA damage.
Gozani
Or
O
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Karuman
Philip
P
Jones
David R
DR
Ivanov
Dmitri
D
Cha
James
J
Lugovskoy
Alexey A
AA
Baird
Cheryl L
CL
Zhu
Hong
H
Field
Seth J
SJ
Lessnick
Stephen L
SL
Villasenor
Jennifer
J
Mehrotra
Bharat
B
Chen
Jian
J
Rao
Vikram R
VR
Brugge
Joan S
JS
Ferguson
Colin G
CG
Payrastre
Bernard
B
Myszka
David G
DG
Cantley
Lewis C
LC
Wagner
Gerhard
G
Divecha
Nullin
N
Prestwich
Glenn D
GD
Yuan
Junying
J
D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism; D000595:Amino Acid Sequence / Q000235:genetics; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D005057:Eukaryotic Cells / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D018398:Homeodomain Proteins; C444654:ING2 protein, human; D018129:Phosphatidylinositol Phosphates; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C113567:phosphatidylinositol 5-phosphate; C040985:phosphatidylinositol receptors; D019870:1-Phosphatidylinositol 4-Kinase