title: Rho-kinase signaling controls nucleocytoplasmic shuttling of class IIa histone deacetylase (HDAC7) and transcriptional activation of orphan nuclear receptor NR4A1.
abstract: Rho-kinase (ROCK) has been well documented to play a key role in RhoA-induced actin remodeling. ROCK activation results in myosin light chain (MLC) phosphorylation either by direct action on MLC kinase (MLCK) or by inhibition of MLC phosphatase (MLCP), modulating actin-myosin contraction. We found that inhibition of the ROCK pathway in induced pluripotent stem cells, leads to nuclear export of HDAC7 and transcriptional activation of the orphan nuclear receptor NR4A1 while in cells with constitutive ROCK hyperactivity due to loss of function of the RhoGTPase activating protein Oligophrenin-1 (OPHN1), the orphan nuclear receptor NR4A1 is downregulated. Our study identify a new target of ROCK signaling via myosin phosphatase subunit (MYPT1) and Histone Deacetylase (HDAC7) at the nuclear level and provide new insights in the cellular functions of ROCK.
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Compagnucci
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Barresi
authors.affiliation: Research Laboratories, Confocal Microscopy Core Facility, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrini
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address: ginevra.zanni@opbg.net.
authors.forename: Ginevra
authors.initials: G
authors.lastname: Zanni
mesh_terms: D021581:Active Transport, Cell Nucleus; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics; D015536:Down-Regulation; D020690:GTPase-Activating Proteins / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics*; D010766:Phosphorylation; D015398:Signal Transduction; D015533:Transcriptional Activation; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D003598:Cytoskeletal Proteins; D020690:GTPase-Activating Proteins; C539821:NR4A1 protein, human; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C111952:OPHN1 protein, human; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; C543273:HDAC7 protein, human; D006655:Histone Deacetylases
keywords: Histone Deacetylase 7; Myosin phosphatase subunit 1; Oligophrenin 1; Orphan nuclear receptor NR4A1; Rho-kinase