Sci. STKE, 15 July 2003
PROTEIN DOMAINS PHD Finger Finds a Partner
The nuclear phosphoinositide (PI) signaling pathways remain less well characterized than the cytosolic PI pathways (see Irvine). Gozani et al. identified ING2, a protein that may link p53 to chromatin remodeling, in a screen for PI-binding proteins. They discovered that the ING2 plant homeodomain (PHD) finger motif, which is a zinc finger motif with no known binding partners, interacted with PIs and showed highest affinity for PI(3)P and PI(5)P. Structural modeling and mutational analysis of the ING2 PHD suggested that two basic regions were required for PI binding. Other PHD fingers from other proteins also bound PIs when used as glutathione S-transferase (GST) fusions to probe lipid blots. Expression of the bacterial protein IpgD, which increases the abundance of PI(5)P at the plasma membrane, along with green fluorescent protein (GFP)-tagged ING2 showed PHD-dependent relocalization of a diffuse cytosolic pool of ING2 to the plasma membrane (ING2 was also prevalent in the nucleus in these cells). In cells overexpressing phosphoinositide kinase IIβ (PIKIIβ), the interaction between endogenous ING2 and the chromatin-nuclear matrix fraction was decreased. The ability of overexpressed ING2 to stimulate p53 acetylation and gene regulatory activity and apoptotic activity was abolished by mutation of the PHD to block lipid binding. RNA interference knock down of ING2 or overexpression of the PHD finger of ING2 to act as a dominant-negative decreased etoposide-induced apoptosis and p53 acetylation. These results together identify a binding partner for the orphan PHD finger and demonstrate that ING2 serves as a link between the nuclear PI cycle and p53 activity.
O. Gozani, P. Karuman, D. R. Jones, D. Ivanov, J. Cha, A. A. Lugovskoy, C. L. Baird, H. Zhu, S. J. Field, S. L. Lessnick, J. Villasenor, B. Mehrotra, J. Chen, V. R. Rao, J. S. Brugge, C. G. Ferguson, B. Payrastre, D. G. Myszka, L. C. Cantley, G. Wagner, N. Divecha, G. D. Prestwich, J. Yuan, The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor. Cell 114, 99-111 (2003). [Online Journal]
Citation: PHD Finger Finds a Partner. Sci. STKE 2003, tw270 (2003).
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