TY - JOUR
T1 - The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor
AU - Gozani, Or
AU - Karuman, Philip
AU - Jones, David R.
AU - Ivanov, Dmitri
AU - Cha, James
AU - Lugovskoy, Alexey A.
AU - Baird, Cheryl L.
AU - Zhu, Hong
AU - Field, Seth J.
AU - Lessnick, Stephen L.
AU - Villasenor, Jennifer
AU - Mehrotra, Bharat
AU - Chen, Jian
AU - Rao, Vikram R.
AU - Brugge, Joan S.
AU - Ferguson, Colin G.
AU - Payrastre, Bernard
AU - Myszka, David G.
AU - Cantley, Lewis C.
AU - Wagner, Gerhard
AU - Divecha, Nullin
AU - Prestwich, Glenn D.
AU - Yuan, Junying
N1 - Funding Information:
We thank E. Appella and S. Saito for antibody AbLys(Ac)382; A.V. Gudkov for Ing1 cDNA; A. Hall for GFP-AKT(PH); and T. Hunter for GST-MEKK1 PHD finger expression construct. We also thank C. Pendaries, H. Tronchere, and P. Sansonetti for the IpgD construct; R.A. Anderson and K. Chua for useful discussion; and M. Boyce and K. Chua for critical reading of the manuscript. This work was supported in part by NIH grants to J.Y. (AG16674), L.C.C. (GM36624), and G.D.P. (GM57705) and (NS29632). O.G. was supported by KO8AG19245 and the Harvard/Hartford Center for Excellence in Geriatric Research and P.K. by a Singapore Cancer Society Grant.
PY - 2003/7/11
Y1 - 2003/7/11
N2 - 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.
AB - 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.
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U2 - 10.1016/S0092-8674(03)00480-X
DO - 10.1016/S0092-8674(03)00480-X
M3 - Article
C2 - 12859901
AN - SCOPUS:0038784526
SN - 0092-8674
VL - 114
SP - 99
EP - 111
JO - Cell
JF - Cell
IS - 1
ER -