title: Notch post-translationally regulates β-catenin protein in stem and progenitor cells.
abstract: Cellular decisions of self-renewal or differentiation arise from integration and reciprocal titration of numerous regulatory networks. Notch and Wnt/β-catenin signalling often intersect in stem and progenitor cells and regulate each other transcriptionally. The biological outcome of signalling through each pathway often depends on the context and timing as cells progress through stages of differentiation. Here, we show that membrane-bound Notch physically associates with unphosphorylated (active) β-catenin in stem and colon cancer cells and negatively regulates post-translational accumulation of active β-catenin protein. Notch-dependent regulation of β-catenin protein did not require ligand-dependent membrane cleavage of Notch or the glycogen synthase kinase-3β-dependent activity of the β-catenin destruction complex. It did, however, require the endocytic adaptor protein Numb and lysosomal activity. This study reveals a previously unrecognized function of Notch in negatively titrating active β-catenin protein levels in stem and progenitor cells.
authors.affiliation: Gladstone Institute of Cardiovascular Disease and Department of Pediatrics, University of California, San Francisco, 1650 Owens Street, San Francisco, California 94158, USA. ckwon13@jhmi.edu
authors.forename: Chulan
authors.initials: C
authors.lastname: Kwon
authors.forename: Paul
authors.initials: P
authors.lastname: Cheng
authors.forename: Isabelle N
authors.initials: IN
authors.lastname: King
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.forename: Lincoln
authors.initials: L
authors.lastname: Shenje
authors.forename: Vishal
authors.initials: V
authors.lastname: Nigam
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D019073:HT29 Cells; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D009419:Nerve Tissue Proteins; C497762:Notch1 protein, mouse; C113026:NUMB protein, human; C106293:Numb protein, mouse; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3