PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner

M. Sjöqvist, D. Antfolk, S. Ferraris, V. Rraklli, C. Haga, C. Antila, A. Mutvei, S.Y. Imanishi, J. Holmberg, S. Jin, J.E. Eriksson, U. Lendahl, C.M. Sahlgren

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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.

Original languageEnglish
Pages (from-to)433-50
Number of pages18
JournalCell
Volume24
Issue number4
DOIs
Publication statusPublished - Apr 2014

Keywords

  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Chick Embryo
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Molecular Sequence Data
  • Protein Kinase C
  • Protein Transport
  • Receptor, Notch1
  • Sequence Homology, Amino Acid
  • Signal Transduction

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    Sjöqvist, M., Antfolk, D., Ferraris, S., Rraklli, V., Haga, C., Antila, C., Mutvei, A., Imanishi, S. Y., Holmberg, J., Jin, S., Eriksson, J. E., Lendahl, U., & Sahlgren, C. M. (2014). PKCζ regulates Notch receptor routing and activity in a Notch signaling-dependent manner. Cell, 24(4), 433-50. https://doi.org/10.1038/cr.2014.34