title: HDAC6 inhibitors modulate Lys49 acetylation and membrane localization of β-catenin in human iPSC-derived neuronal cells.
abstract: We examined the effects of isoform-specific histone deacetylase (HDAC) inhibitors on β-catenin posttranslational modifications in neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs). β-catenin is a multifunctional protein with important roles in the developing and adult central nervous system. Activation of the Wnt pathway results in stabilization and nuclear translocation of β-catenin, resulting in activation of multiple target genes. In addition, β-catenin forms a complex with cadherins at the plasma membrane as part of the adherens junctions. The N-terminus of β-catenin has phosphorylation, ubiquitination, and acetylation sites that regulate its stability and signaling. In the absence of a Wnt signal, Ser33, Ser37, and Thr41 are constitutively phosphorylated by glycogen synthase kinase 3β (GSK3β). β-Catenin phosphorylated at these sites is recognized by β-transducin repeat-containing protein (βTrCP), which results in ubiquitination and degradation by the ubiquitin-proteasome pathway. The N-terminal regulatory domain of β-catenin also includes Ser45, a phosphorylation site for Casein Kinase 1α (CK1α) and Lys49, which is acetylated by the acetyltransferase p300/CBP-associated factor (PCAF). The relevance of Lys49 acetylation and Ser45 phosphorylation to the function of β-catenin is an active area of investigation. We find that HDAC6 inhibitors increase Lys49 acetylation and Ser45 phosphorylation but do not affect Ser33, Ser37, and Thr41 phosphorylation. Lys49 acetylation results in decreased ubiquitination of β-catenin in the presence of proteasome inhibition. While increased Lys49 acetylation does not affect total levels of β-catenin, it results in increased membrane localization of β-catenin.
authors.affiliation: †Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, United States.|‡Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Iaconelli
authors.affiliation: †Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, United States.|‡Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, United States.
authors.forename: Joanne H
authors.initials: JH
authors.lastname: Huang
authors.affiliation: †Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, United States.|‡Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, United States.
authors.forename: Shaunna S
authors.initials: SS
authors.lastname: Berkovitch
authors.affiliation: ‡Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, United States.|∥MGH Cancer Center, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, United States.
authors.forename: Shrikanta
authors.initials: S
authors.lastname: Chattopadhyay
authors.affiliation: ‡Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, United States.|⊥Center for Systems Biology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, United States.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.affiliation: ‡Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, United States.|#Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
authors.affiliation: †Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, United States.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Haggarty
authors.affiliation: †Center for Experimental Drugs and Diagnostics, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, United States.|‡Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, United States.|§Schizophrenia and Bipolar Disorder Program, McLean Hospital, Belmont, Massachusetts 02478, United States.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Karmacharya
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D002454:Cell Differentiation; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D054875:Ubiquitination; D051176:beta Catenin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases; D008239:Lysine