title: Ck2-Dependent Phosphorylation Is Required to Maintain Pax7 Protein Levels in Proliferating Muscle Progenitors.
abstract: Skeletal muscle regeneration and long term maintenance is directly link to the balance between self-renewal and differentiation of resident adult stem cells known as satellite cells. In turn, satellite cell fate is influenced by a functional interaction between the transcription factor Pax7 and members of the MyoD family of muscle regulatory factors. Thus, changes in the Pax7-to-MyoD protein ratio may act as a molecular rheostat fine-tuning acquisition of lineage identity while preventing precocious terminal differentiation. Pax7 is expressed in quiescent and proliferating satellite cells, while its levels decrease sharply in differentiating progenitors Pax7 is maintained in cells (re)acquiring quiescence. While the mechanisms regulating Pax7 levels based on differentiation status are not well understood, we have recently described that Pax7 levels are directly regulated by the ubiquitin-ligase Nedd4, thus promoting proteasome-dependent Pax7 degradation in differentiating satellite cells. Here we show that Pax7 levels are maintained in proliferating muscle progenitors by a mechanism involving casein kinase 2-dependent Pax7 phosphorylation at S201. Point mutations preventing S201 phosphorylation or casein kinase 2 inhibition result in decreased Pax7 protein in proliferating muscle progenitors. Accordingly, this correlates directly with increased Pax7 ubiquitination. Finally, Pax7 down regulation induced by casein kinase 2 inhibition results in precocious myogenic induction, indicating early commitment to terminal differentiation. These observations highlight the critical role of post translational regulation of Pax7 as a molecular switch controlling muscle progenitor fate.
authors.affiliation: Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Natalia
authors.initials: N
authors.lastname: González
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Moresco
authors.affiliation: Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Cabezas
authors.affiliation: Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Eduardo
authors.initials: E
authors.lastname: de la Vega
authors.affiliation: Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Francisco
authors.initials: F
authors.lastname: Bustos
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Hugo C
authors.initials: HC
authors.lastname: Olguín
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D051379:Mice; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology*; D017570:MyoD Protein / Q000378:metabolism; D051763:PAX7 Transcription Factor / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology*; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology
chemical_list: D017570:MyoD Protein; D051763:PAX7 Transcription Factor; C497322:Pax7 protein, mouse; D047390:Casein Kinase II