Molecular and Cellular Pathobiology PIPKIg Regulates b-Catenin Transcriptional Activity Downstream of Growth Factor Receptor Signaling

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