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 | English |
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Pages (from-to) | 433-50 |
Number of pages | 18 |
Journal | Cell |
Volume | 24 |
Issue number | 4 |
DOIs | |
Publication status | Published - 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