title: p300/β-Catenin Interactions Regulate Adult Progenitor Cell Differentiation Downstream of WNT5a/Protein Kinase C (PKC).
abstract: Maintenance of stem/progenitor cell-progeny relationships is required for tissue homeostasis during normal turnover and repair. Wnt signaling is implicated in both maintenance and differentiation of adult stem/progenitor cells, yet how this pathway serves these dichotomous roles remains enigmatic. We previously proposed a model suggesting that specific interaction of β-catenin with either of the homologous Kat3 co-activators, p300 or CREB-binding protein, differentially regulates maintenance versus differentiation of embryonic stem cells. Limited knowledge of endogenous mechanisms driving differential β-catenin/co-activator interactions and their role in adult somatic stem/progenitor cell maintenance versus differentiation led us to explore this process in defined models of adult progenitor cell differentiation. We focused primarily on alveolar epithelial type II (AT2) cells, progenitors of distal lung epithelium, and identified a novel axis whereby WNT5a/protein kinase C (PKC) signaling regulates specific β-catenin/co-activator interactions to promote adult progenitor cell differentiation. p300/β-catenin but not CBP/β-catenin interaction increases as AT2 cells differentiate to a type I (AT1) cell-like phenotype. Additionally, p300 transcriptionally activates AT1 cell-specific gene Aqp-5. IQ-1, a specific inhibitor of p300/β-catenin interaction, prevents differentiation of not only primary AT2 cells, but also tracheal epithelial cells, and C2C12 myoblasts. p300 phosphorylation at Ser-89 enhances p300/β-catenin interaction, concurrent with alveolar epithelial cell differentiation. WNT5a, a traditionally non-canonical WNT ligand regulates Ser-89 phosphorylation and p300/β-catenin interactions in a PKC-dependent manner, likely involving PKCζ. These studies identify a novel intersection of canonical and non-canonical Wnt signaling in adult progenitor cell differentiation that has important implications for targeting β-catenin to modulate adult progenitor cell behavior in disease.
authors.affiliation: From the Department of Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Rieger
authors.affiliation: From the Department of Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
authors.forename: Beiyun
authors.initials: B
authors.lastname: Zhou
authors.affiliation: From the Department of Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine.
authors.forename: Nicola
authors.initials: N
authors.lastname: Solomon
authors.affiliation: From the Department of Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Sunohara
authors.affiliation: the Departments of Pediatrics, Division of Neonatology.
authors.forename: Changgong
authors.initials: C
authors.lastname: Li
authors.affiliation: Biochemistry and Molecular Biology, and.
authors.forename: Cu
authors.initials: C
authors.lastname: Nguyen
authors.affiliation: From the Department of Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: the Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri 63110, and.
authors.forename: Jie-hong
authors.initials: JH
authors.lastname: Pan
authors.affiliation: the Departments of Pediatrics, Division of Neonatology.
authors.forename: Parviz
authors.initials: P
authors.lastname: Minoo
authors.affiliation: From the Department of Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Pathology, the Department of Chemical Engineering and Materials Science, Viterbi School of Engineering, University of Southern California, Los Angeles, California 90089.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Crandall
authors.affiliation: the Department of Medicine, School of Medicine, Washington University, St. Louis, Missouri 63110, and.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Brody
authors.affiliation: Biochemistry and Molecular Biology, and the Center for Molecular Pathways and Drug Discovery, and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
authors.affiliation: From the Department of Medicine, Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Biochemistry and Molecular Biology, and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, zborok@med.usc.edu.
authors.forename: Zea
authors.initials: Z
authors.lastname: Borok
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D056809:Alveolar Epithelial Cells / Q000502:physiology; D000818:Animals; D051402:Aquaporin 5 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D050881:E1A-Associated p300 Protein / Q000502:physiology*; D017097:Electric Impedance; D015870:Gene Expression; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D051381:Rats; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000502:physiology*
chemical_list: C496040:Aqp5 protein, rat; D051402:Aquaporin 5; C495268:Ctnnb1 protein, rat; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C491837:Wnt5a protein, rat; D051176:beta Catenin; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat; D011493:Protein Kinase C
keywords: Wnt pathway; beta-catenin (β-catenin); differentiation; p300; protein kinase C (PKC); protein-protein interaction
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