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

Marika Sjöqvist, Daniel Antfolk, Saima Ferraris, V Rraklli, Cecilia Haga, Christian Antila, A Mutvei, Susumu Imanishi, J Holmberg, S Jin, John Eriksson, U Lendahl, Cecilia Sahlgren

Research output: Contribution to journalArticleScientificpeer-review

30 Citations (Scopus)

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 languageUndefined/Unknown
Pages (from-to)433–450
JournalCell Research
Volume24
Issue number4
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

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