A Ligand-Induced Extracellular Cleavage Regulates γ-Secretase-like Proteolytic Activation of Notch1

Mumm, Jeff S.; Schroeter, Eric H.; Saxena, Mohit; Griesemer, Adam; Tian, Xiaolin; Pan, Duojia; Ray, William J.; Kopan, Raphael

doi:10.1016/s1097-2765(00)80416-5

Cited by 796 publications

(711 citation statements)

References 53 publications

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“…The requirement for ligand-dependent processing for Notch activity was verified using mutants disabled for interactions with ligand. The recombinant Notch1 LNG , which lacks the epidermal growth factor (EGF)-like repeats in its extracellular domain, 20 did not block death (Figure 2b), whereas a construct corrected for this defect (Notch1 LNG CCbSS ) imparted Figure 1 Characterization of the apoptotic response to neglect in HeLa cells. (a) Confocal image of HeLa cells cultured in complete medium (CM; nutrient replete) or buffered saline (neglect).…”

Section: Resultsmentioning

confidence: 99%

A hierarchical cascade activated by non-canonical Notch signaling and the mTOR–Rictor complex regulates neglect-induced death in mammalian cells

et al. 2009

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The regulation of cellular metabolism and survival by trophic factors is not completely understood. Here, we describe a signaling cascade activated by the developmental regulator Notch, which inhibits apoptosis triggered by neglect in mammalian cells. In this pathway, the Notch intracellular domain (NIC), which is released after interaction with ligand, converges on the kinase mammalian target of rapamycin (mTOR) and the substrate-defining protein rapamycin independent companion of mTOR (Rictor), culminating in the activation of the kinase Akt/PKB. Biochemical and molecular approaches using site-directed mutants identified AktS473 as a key downstream target in the antiapoptotic pathway activated by NIC. Despite the demonstrated requirement for Notch processing and its predominant nuclear localization, NIC function was independent of CBF1/RBP-J, an essential DNA-binding component required for canonical signaling. In experiments that placed spatial constraints on NIC, enforced nuclear retention abrogated antiapoptotic activity and a membrane-anchored form of NIC-blocked apoptosis through mTOR, Rictor and Akt-dependent signaling. We show that the NIC-mTORC2-Akt cascade blocks the apoptotic response triggered by removal of medium or serum deprivation. Consistently, membrane-tethered NIC, and AktS473 inhibited apoptosis triggered by cytokine deprivation in activated T cells. Thus, this study identifies a non-canonical signaling cascade wherein NIC integrates with multiple pathways to regulate cell survival.

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Section: Resultsmentioning

confidence: 99%

A hierarchical cascade activated by non-canonical Notch signaling and the mTOR–Rictor complex regulates neglect-induced death in mammalian cells

et al. 2009

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“…Previous work demonstrated that EGF11 and EGF12 are the required elements for Notch1 to be able to recognize its ligands Jagged and DLL 15. Ligand binding leads to the cleavage at the juxtamembrane region (site S2) of Notch by ADAM (a disintegrin and metalloprotease) protease 16, 17. Shedding of the Notch extracellular domain facilitates subsequent intramembranous cleavage of Notch by γ ‐secretase complex, generating Notch intracellular domain (NICD or ICN)18, 19.…”

Section: Notch Signalingmentioning

confidence: 99%

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

et al. 2016

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The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro‐oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers.

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“…Activation PS-RIP of several type I membrane receptors such as Notch and ErbB4 is regulated by ligand stimulation (Brou et al, 2000;Mumm et al, 2000;Ni et al, 2001). Therefore, we cotreated MDCK cells with a proteasome and ␥-secretase inhibitors to stabilize Met-CTF and stimulated the cells with HGF/SF ( Figure 5A).…”

Section: Sequential Proteolysis Of Met Is Independent Of Kinasementioning

confidence: 99%

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

Foveau

Ancot

Leroy

et al. 2009

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113

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A Ligand-Induced Extracellular Cleavage Regulates γ-Secretase-like Proteolytic Activation of Notch1

Cited by 796 publications

References 53 publications

A hierarchical cascade activated by non-canonical Notch signaling and the mTOR–Rictor complex regulates neglect-induced death in mammalian cells

A hierarchical cascade activated by non-canonical Notch signaling and the mTOR–Rictor complex regulates neglect-induced death in mammalian cells

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

Down-Regulation of the Met Receptor Tyrosine Kinase by Presenilin-dependent Regulated Intramembrane Proteolysis

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