Inositol pentakisphosphate mediates Wnt/beta-catenin signaling.
Wnt3a stimulates lymphoid enhancer factor/T-cell factor protein-sensitive transcription, i.e. the canonical pathway, in mouse F9 embryonal tetratocarcinoma cells expressing rat Frizzled-1. We explored the potential roles for inositol polyphosphates as mediators of Wnt signaling in the canonical path-way. Wnt3a triggers G-protein-linked phosphatidylinositol signaling, transiently generating inositol polyphosphates, especially inositol pentakisphosphate (IP(5)) accumulation. Knock-down of Galpha(q) abolishes, whereas expression of the Q209L constitutively active mutant of Galpha(q) mimics, the effects of Wnt3a on IP(5) generation and downstream signaling. Phospholipase Cbeta-1 and Cbeta-3 mediate the G protein signal to the level of phosphatidylinositol signaling. Knock-down and inhibitor studies of the enzymes responsible for generating IP(5) reveal inositol 1,4,5-trisphosphate 3-kinase and inositol polyphosphate multikinase as key mediators in the production of IP(5). Wnt3a stimulation of the canonical pathway requires accumulation of IP(5), which acts to inhibit the activity of glycogen synthase kinase-3beta, whereas stimulating casein kinase 2. Blockade of Wnt3a stimulation of IP(5) generation blocks beta-catenin accumulation, activation of lymphoid enhancer factor/T-cell factor protein-sensitive transcription, and promotion of primitive endoderm formation in response to Wnt3a. Phosphatidylinositol signaling mediates Wnt3a action in the canonical pathway, acting to generate inositol pentakisphosphate, a key second messenger of Wnt3a.
Gao
Yuan
Y
Department of Physiology and Biophysics, Diabetes and Metabolic Disease Research Center, School of Medicine, Health Sciences Center, State University of New York, Stony Brook, New York 11794-8661, USA.
Wang
Hsien-yu
HY
D019943:Amino Acid Substitution; D000818:Animals; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004707:Endoderm / Q000166:cytology / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007295:Inositol Phosphates / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020125:Mutation, Missense; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000235:genetics / Q000378:metabolism; D015290:Second Messenger Systems / Q000502:physiology*; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D051157:Frizzled Receptors; D007295:Inositol Phosphates; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; D051820:TCF Transcription Factors; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; C078603:Fzd1 protein, rat; C013571:inositol pentaphosphate; D019869:Phosphatidylinositol 3-Kinases; D047390:Casein Kinase II; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D043802:GTP-Binding Protein alpha Subunits, Gq-G11