High levels of Notch signaling down-regulate Numb and Numblike

Chapman, Gavin; Liu, Lining; Sahlgren, Cecilia; Dahlqvist, Camilla; Lendahl, Urban

doi:10.1083/jcb.200602009

Cited by 77 publications

(78 citation statements)

References 21 publications

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“…FIH-1 acts as a negative regulator of Notch signaling in transcriptional assays and also accelerates myogenic differentiation in C2C12 cells. These results are in excellent agreement with negative control of Notch signaling, and other negative regulators of Notch, such as Numb and Numblike, similarly promote myogenic differentiation (14).…”

Section: Discussionsupporting

confidence: 79%

Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways

Zheng

Linke²,

Dias³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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240

258

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gene regulation ͉ hydroxylation ͉ signal transduction R educed oxygen levels (hypoxia) lead to a set of cellular adaptations, including increased angiogenesis and erythropoiesis and a switch to glycolytic metabolism. The cellular machinery that senses hypoxia is composed of several proteins. A critical component is the transcription factor hypoxiainducible factor 1␣ (HIF-1␣) (1). The level and activity of HIF-1␣ are controlled by oxygen-dependent prolyl (PHD) and asparaginyl factor-inhibiting HIF-1␣ (FIH-1)] hydroxylases. PHDs hydroxylate two proline residues in the degradation domain of HIF-1␣ in normoxia, which makes HIF-1␣ a substrate for the von Hippel-Lindau E3 ubiquitin ligase and proteasomal degradation. After stabilization in hypoxia, HIF-1␣ interacts with aryl hydrocarbon receptor nuclear translocator (ARNT) to bind to hypoxia response elements (HREs)

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Section: Discussionsupporting

confidence: 79%

Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways

Zheng

Linke²,

Dias³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

240

258

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“…Notch signaling was activated in 293 HEK cells stably expressing the full-length Notch1 (293FLN1) by culturing the cells on immobilized Jagged1 ligand, and the downstream signaling was measured by a reporter construct with multimerized CSL-binding sites linked to the luciferase gene (12×CSL-luc) [45]. 12×CSL-luc reporter activity was enhanced by culturing the 293FLN1 cells on immobilized Fc-Jagged1 as compared to FcIgG as control, and transfection of a constitutively active form of PKCζ (caPKCζ) led to a further increase in reporter activity ( Figure 3A).…”

Section: Apkcζ Increases Production Of Nicd Enhances Notch Signalingmentioning

confidence: 99%

“…Notch keeps myogenic progenitors in an undifferentiated state and blocks differentiation to myotubes [45,51,52]. We next tested whether the phosphorylation of Notch1 at S1791 by aPKCζ was important for Notch1 control of myogenic differentiation.…”

Section: An Apkcζ Phosphorylation-deficient Notch1∆e Mutant Does Not mentioning

confidence: 99%

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

et al. 2014

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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.

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“…98 Numb is a known negative regulator of Notch which, in turn, may exert a reciprocal negative regulation on Numb. 102 It is thought that Numb, a membrane-tethered adaptor protein, promotes Notch degradation through endocytosis and ubiquitination. 103 It is interesting that pharmacological inhibition of Notch1 in primary tumor cells from breast cancers with reduced Numb levels suppressed their proliferative potential.…”

Section: Notch Myc and Breast Cancermentioning

confidence: 99%