title: PIPKIγ regulates β-catenin transcriptional activity downstream of growth factor receptor signaling.
abstract: Increased β-catenin transcriptional activity downstream of the Wnt/Wingless signaling pathway has been observed in many human tumors, most notably colorectal carcinomas. However, β-catenin activation is also observed in many human malignancies with no observable Wnt activity. Wnt-independent pathways that activate β-catenin remain undefined, yet have the potential to play a significant role during tumorigenesis. Here, we report that phosphotidylinositol phosphate kinase Iγ (PIPKIγ), an enzyme that generates phosphoinositide messengers in vivo, directly associates with β-catenin and increases β-catenin activity downstream of growth factor stimulation. PIPKIγ expression and kinase activity enhance β-catenin phosphorylation on residues that promote nuclear importation and transcriptional activity. Lastly, we show that β-catenin is required for PIPKIγ-dependent increased cell proliferation. These results reveal a novel mechanism in which PIPKIγ expression and catalytic activity enhance β-catenin nuclear translocation and expression of its target genes to promote tumorigenic phenotypes.
authors.affiliation: Department of Pharmacology, School of Medicine and Public Health, and Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Schramp
authors.forename: Narendra
authors.initials: N
authors.lastname: Thapa
authors.forename: Jessica
authors.initials: J
authors.lastname: Heck
authors.forename: Richard
authors.initials: R
authors.lastname: Anderson
mesh_terms: D015820:Cadherins / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology*
chemical_list: D015820:Cadherins; D034741:RNA, Small Interfering; D017978:Receptors, Growth Factor; D051176:beta Catenin; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase