title: PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner.
abstract: Activation of Notch signaling requires intracellular routing of the receptor, but the mechanisms controlling the distinct steps in the routing process is poorly understood. We identify PKCζ as a key regulator of Notch receptor intracellular routing. When PKCζ was inhibited in the developing chick central nervous system and in cultured myoblasts, Notch-stimulated cells were allowed to undergo differentiation. PKCζ phosphorylates membrane-tethered forms of Notch and regulates two distinct routing steps, depending on the Notch activation state. When Notch is activated, PKCζ promotes re-localization of Notch from late endosomes to the nucleus and enhances production of the Notch intracellular domain, which leads to increased Notch activity. In the non-activated state, PKCζ instead facilitates Notch receptor internalization, accompanied with increased ubiquitylation and interaction with the endosomal sorting protein Hrs. Collectively, these data identify PKCζ as a key regulator of Notch trafficking and demonstrate that distinct steps in intracellular routing are differentially modulated depending on Notch signaling status.
authors.affiliation: 1] Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland [2] Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Marika
authors.initials: M
authors.lastname: Sjöqvist
authors.affiliation: 1] Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland [2] Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Antfolk
authors.affiliation: Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Saima
authors.initials: S
authors.lastname: Ferraris
authors.affiliation: Ludwig Institute for Cancer Research, Karolinska Institute, Box 240, SE-171 77 Stockholm, Sweden.
authors.forename: Vilma
authors.initials: V
authors.lastname: Rraklli
authors.affiliation: 1] Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland [2] Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Haga
authors.affiliation: 1] Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland [2] Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Christian
authors.initials: C
authors.lastname: Antila
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Mutvei
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
authors.forename: Susumu Y
authors.initials: SY
authors.lastname: Imanishi
authors.affiliation: 1] Ludwig Institute for Cancer Research, Karolinska Institute, Box 240, SE-171 77 Stockholm, Sweden [2] Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Holmberg
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Shaobo
authors.initials: S
authors.lastname: Jin
authors.affiliation: 1] Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland [2] Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland.
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
authors.affiliation: 1] Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland [2] Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland [3] Department of Biomedical Engineering, Technical University of Eindhoven, 2612 Eindhoven, The Netherlands.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sahlgren
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011493:Protein Kinase C / Q000502:physiology*; D021381:Protein Transport; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000235:genetics
chemical_list: D051881:Receptor, Notch1; C081975:protein kinase C eta; D011493:Protein Kinase C