Volume 24, No 4, Apr 2014

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 24 Issue 4, April 2014: 433-450

ORIGINAL ARTICLES

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

Marika Sjöqvist^1,2,*, Daniel Antfolk^1,2,*, Saima Ferraris², Vilma Rraklli³, Cecilia Haga^1,2, Christian Antila^1,2, Anders Mutvei⁴, Susumu Y Imanishi¹, Johan Holmberg^3,4, Shaobo Jin⁴, John E Eriksson^1,2, Urban Lendahl⁴ and Cecilia Sahlgren^1,2,5

¹Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, 20520 Turku, Finland
²Department of Biosciences, Åbo Akademi University, 20520 Turku, Finland
³Ludwig Institute for Cancer Research, Karolinska Institute, Box 240, SE-171 77 Stockholm, Sweden
⁴Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
5Department of Biomedical Engineering, Technical University of Eindhoven, 2612 Eindhoven, The Netherlands Correspondence: Cecilia Sahlgren,(cecilia.sahlgren@btk.fi)

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.

10.1038/cr.2014.34

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