The PHD Finger of the Chromatin-Associated Protein ING2 Functions as a Nuclear Phosphoinositide Receptor

Abstract

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.

MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells

“…PHD fingers are present in many chromatin regulators (Saha et al, 1995). As PHD fingers have the potential to bind phosphoinositides and are implicated in nuclear lipid signaling (Gozani et al, 2003), an interesting possibility is that phosphoinositides bind directly to MOZ and MORF complexes and regulate their activity. PHD fingers may also function as methyl-lysine-binding modules.…”

Nuclear inositol lipid metabolism: More than just second messenger generation?

“…Most significantly for this review, ASH2 contains a PHD finger, i.e., a putative double zinc finger involved in mediating protein-protein interactions and modifying chromatin structure. Furthermore, PHD fingers may act as domains capable of binding nuclear polyphosphoinositides [Gozani et al, 2003]. Both SKTL and ASH2 accumulate on polytene chromosomes.…”

“…Nevertheless, in the absence of NGF treatment all the nuclei displayed DNA degradation, suggesting that Akt activation alone is not sufficient to inhibit DNA cleavage. The down-stream effectors of nuclear PtdIns (3,4,5)P 3 which prevent apoptosis have yet to be identified, however it should be emphasized that nuclear PtdIns(5)P modulates p53 activity and cell death through the interaction with its nuclear receptor ING2 [Gozani et al, 2003]. …”

Determining selectivity of phosphoinositide-binding domains

“…Of the 13 most populous classes of signaling interaction domain found in the human proteome [3], members of more than half have been reported to drive reversible membrane association by such interactions [1,2,4,5]. Domains that have been implicated in head group-specific recognition of phosphoinositides include pleckstrin homology (PH) domains [6,7]; phagocyte oxidase (phox) homology (PX) domains [8]; FYVE domains (for Fab1, YOTB, Vac1 and EEA1) [9]; epsin or AP180 N-terminal homology (ENTH/ANTH) domains [10,11]; and plant homeodomain (PHD) zinc fingers [12]. In addition, phosphoinositide binding has been reported for PDZ (for Postsynaptic density protein, Disc large, Zona occludens) domains [13], FERM (for band Four-point-one, Ezrin, Radixin, Moesin) domains [14], Tubby [15], and MARCKS [16] proteins.…”