PIPKIγ Regulates β-Catenin Transcriptional Activity Downstream of Growth Factor Receptor Signaling

Increased beta-catenin transcriptional activity downstream of the Wnt/Wingless signaling pathway has been observed in many human tumors, most notably colorectal carcinomas. However, beta-catenin activation is also observed in many human malignancies with no observable Wnt activity. Wnt-independent pathways that activate beta-catenin remain undefined, yet have the potential to play a significant role during tumorigenesis. Here, we report that phosphotidylinositol phosphate kinase I gamma (PIPKI gamma), an enzyme that generates phosphoinositide messengers in vivo, directly associates with beta-catenin and increases beta-catenin activity downstream of growth factor stimulation. PIPKI gamma expression and kinase activity enhance beta-catenin phosphorylation on residues that promote nuclear importation and transcriptional activity. Lastly, we show that beta-catenin is required for PIPKI gamma-dependent increased cell proliferation. These results reveal a novel mechanism in which PIPKI gamma expression and catalytic activity enhance beta-catenin nuclear translocation and expression of its target genes to promote tumorigenic phenotypes. Cancer Res; 71(4); 1282-91. (C) 2011 AACR.