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

Onderzoeksoutput: Bijdrage aan tijdschriftTijdschriftartikelAcademicpeer review

31 Citaten (Scopus)
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Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)433-50
Aantal pagina's18
TijdschriftCell
Volume24
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - apr 2014

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