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 language | Undefined/Unknown |
|---|---|
| Pages (from-to) | 433–450 |
| Journal | Cell Research |
| Volume | 24 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2014 |
| MoE publication type | A1 Journal article-refereed |
Funding
This work was supported by Academy of Finland (CS, SYI), Center of Excellence in Cell stress and Molecular Aging, Åbo Akademi (DA), Turku Graduate School for Biomedical Sciences (MS), the Swedish Cancer Society, the Swedish Research Council (DBRM, StratRegen and Project Grant), Karolinska Institute (BRECT, Theme Center in Regenerative Medicine and a Distinguished Professor Award to UL). We are grateful to Helena Saarento for technical assistance. We thank the Cell Imaging Core at Turku Centre for Biotechnology and the proteomics facility of the MRC Protein Phosphorylation Unit, University of Dundee.