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PKC? regulates Notch receptor routing and activity in a Notch signaling-dependent manner.

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 PKC? as a key regulator of Notch receptor intracellular routing. When PKC? was inhibited in the developing chick central nervous system and in cultured myoblasts, Notch-stimulated cells were allowed to undergo differentiation. PKC? phosphorylates membrane-tethered forms of Notch and regulates two distinct routing steps, depending on the Notch activation state. When Notch is activated, PKC? 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, PKC? instead facilitates Notch receptor internalization, accompanied with increased ubiquitylation and interaction with the endosomal sorting protein Hrs. Collectively, these data identify PKC? as a key regulator of Notch trafficking and demonstrate that distinct steps in intracellular routing are differentially modulated depending on Notch signaling status.

SUBMITTER: Sjoqvist M

PROVIDER: S-EPMC3975507 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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

Sjöqvist Marika M Antfolk Daniel D Ferraris Saima S Rraklli Vilma V Haga Cecilia C Antila Christian C Mutvei Anders A Imanishi Susumu Y SY Holmberg Johan J Jin Shaobo S Eriksson John E JE Lendahl Urban U Sahlgren Cecilia C

Cell research 20140325 4

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 ...[more]

PMID: 24662486

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Project description:Cannabinoid CB(1) receptors (CB(1)Rs) mediate the effects of ?(9)-tetrahydrocannabinol (THC), the psychoactive component in marijuana. Repeated THC administration produces tolerance and dependence, which limit therapeutic development. Moreover, THC produces motor and psychoactive side effects. ?-arrestin2 mediates receptor desensitization, internalization, and signaling, but its role in these CB(1)R effects and receptor regulation is unclear.CB(1)R signaling and behaviors (antinociception, hypothermia, catalepsy) were assessed in ?-arrestin2-knockout (?arr2-KO) and wild-type mice after THC administration. Cannabinoid-stimulated [(35)S]GTP?S and [(3)H]ligand autoradiography were assessed by statistical parametric mapping and region-of-interest analysis.?-arrestin2 deletion increased CB(1)R-mediated G-protein activity in subregions of the cortex but did not affect CB(1)R binding, in vehicle-treated mice. ?arr2-KO mice exhibited enhanced acute THC-mediated antinociception and hypothermia, with no difference in catalepsy. After repeated THC administration, ?arr2-KO mice showed reduced CB(1)R desensitization and/or downregulation in cerebellum, caudal periaqueductal gray, and spinal cord and attenuated tolerance to THC-mediated antinociception. In contrast, greater desensitization was found in hypothalamus, cortex, globus pallidus, and substantia nigra of ?arr2-KO compared with wild-type mice. Enhanced tolerance to THC-induced catalepsy was observed in ?arr2-KO mice.?-arrestin2 regulation of CB(1)R signaling following acute and repeated THC administration was region-specific, and results suggest that multiple, overlapping mechanisms regulate CB(1)Rs. The observations that ?arr2-KO mice display enhanced antinociceptive responses to acute THC and decreased tolerance to the antinociceptive effects of the drug, yet enhanced tolerance to catalepsy, suggest that development of cannabinoid drugs that minimize CB(1)R interactions with ?-arrestin2 might produce improved cannabinoid analgesics with reduced motor suppression.

Dataset Information

PKC? regulates Notch receptor routing and activity in a Notch signaling-dependent manner.

Publications

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

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