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Gamma secretase complex and DOCK2 affinity interactome.

ABSTRACT: γ-secretase is a transmembrane protease complex responsible for processing multiple type I transmembrane proteins, including the amyloid precursor protein and NOTCH. Despite various γ-secretase inhibitors and modulators developed in the past decades to target Notch-dependent cancers, their clinical use is still limited due to the low substrate specificity and on-target gut toxicity. Using a proteomics-based screening approach, we found that the dedicator of cytokinesis protein 2 (DOCK2) interacts with the γ-secretase complex component Nicastrin, regulating Nicastrin N45-mannosidation and γ-secretase activity towards NOTCH receptors.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Acute Leukemia

SUBMITTER: bian weixiang

LAB HEAD: Xu Li

PROVIDER: PXD057036 | Pride | 2026-07-31

REPOSITORIES: Pride

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			Action	DRS
	APH1A_1.mzid.gz	Mzid
	APH1A_1.mzid_APH1A_1.MGF	Mzid
	APH1A_1.raw	Raw
	APH1A_1.sf3	Other
	APH1A_2.mzid.gz	Mzid

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Gamma secretase complex and DOCK2 affinity interactome

Project description:γ-Secretase is a transmembrane protease complex responsible for processing multiple type I transmembrane proteins, including the amyloid precursor protein (APP) and NOTCH. Using a proteomics-based screening approach, we found that dedicator of cytokinesis protein 2 (DOCK2) interacts with the γ-secretase complex component Nicastrin (NCSTN), regulating NCSTN N45-mannosylation and the effects of γ-secretase on NOTCH receptors. Both genetically depleting DOCK2 and pharmacologically targeting NCSTN mannosylation via Kifunensine ameliorate Notch-dependent leukemia progression in vivo. Together, these results reveal a mechanism by which γ-secretase specifically recognizes its substrate and provide a direction for treating Notch-related diseases.

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Targeting Mannosylation of Nicastrin N-glycans Attenuates γ-Secretase Activity and Notch-dependent Leukemia Progression

Project description:γ-Secretase is a transmembrane protease complex that cleaves multiple type I transmembrane proteins, including amyloid precursor protein and NOTCH. Although numerous γ-secretase inhibitors and modulators targeting Notch-dependent cancers have been developed in recent decades, their clinical translation has been hampered by low substrate specificity and on-target gut toxicity. Using a proteomics-based screening approach, we identified dedicator of cytokinesis protein 2 (DOCK2) as an interactor of the γ-secretase subunit Nicastrin (NCSTN). We further demonstrate that DOCK2 regulates mannosylation of NCSTN N-glycans, which in turn modulates γ-secretase activity toward NOTCH receptors. Both genetic depletion of DOCK2 and pharmacological inhibition of NCSTN mannosylation with Kifunensine attenuated Notch-dependent leukemia progression in vivo. Collectively, these findings uncover a regulatory mechanism underlying substrate-specific activation of γ-secretase and suggest a promising therapeutic strategy for Notch-related diseases.

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Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma

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Expression data from mouse E14.5 fetal liver SLAM LSKs

Project description:To determine genes in FL HSCs that are sensitive to Notch signagling, E14.5 FL cells were cultured on DL1( to stimulate Notch signaling). Cells were cultured in the presence of DMSO (vehicle control) or gamma secretase inhibitor (1uM) for 4 hrs or 10hrs. Gamma secretase inhibitor was used to inhibit Notch signaling. SLAM-LSKs were sorted and used for RNA preparation.

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Histone variant H2A.Z deposition and acetylation directs the canonical Notch signaling response

Project description:The study deals with the elucidation of potential interaction partners of the intracellular domain of the transmembrane receptor Notch1, termed NICD. The NICD is released from the cytoplasmic tail of the Notch receptor by gamma-secretase treatment and translocated as a transcription factor to the nucleus. Here, virally transduced recombinant NICD constructs (wild-type and deltaEP hyperactive mutant) were employed for AP-MS with the aim of identifying novel NICD interactors in a murine T cell leukemia cell line.

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Identification of naturally short gamma-secretase substrates

Project description:The intramembrane protease gamma-secretase has broad physiological functions, but also contributes to Notch-dependent tumors and Alzheimer’s disease. To identify naturally short substrates and non-substrates of gamma-secretase, we used four human cell lines of different tissue origins, breast cancer MCF7 cells, cervix carcinoma HeLa cells, T cell leukemia Jurkat cells and lymphoma U937 macrophage-like cells. The cell lines were treated overnight with the established gamma-secretase inhibitor DAPT or DMSO as a control. The proteomes of membrane fractions were determined by nano-liquid chromatography-tandem mass spectrometry and label-free quantitative proteomics. TNFRSF12A, PTPRCAP and C16orf54 were identified as potential naturally short gamma-secretase substrates, whereas other proteins with a short ectodomain including ‘pituitary tumor-transforming gene 1-interacting protein’ (PTTG1IP) did not show an increased abundance upon DAPT treatment.

2024-05-24 | PXD045701 | Pride

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Project description:γ-secretase is an intra-membrane-cleaving aspartyl protease implicated in the processing of a wide range of type I membrane proteins including the Notch receptor and the amyloid-β precursor protein (APP). It thus regulates a diverse array of cellular and biological processes including the differentiation of neuronal embryonic stem cells, or intestinal stem cells, with the latter controlling the self-renewing of the intestinal epithelium. Indeed, proteolysis of these proteins by γ-secretase triggers signaling cascades by releasing intracellular domains (ICDs) which, following association with adaptor proteins and nuclear translocation, modulate the transcription of different genes by binding directly to their promoters. The pronounced proliferative and regenerative effects of Notch signaling and its implication in the generation of the Aβ-peptides, makes γ-secretase a therapeutic target for several types of cancer and for Alzheimer’s disease. To investigate the broad effects of γ-secretase activity onto the cellular transcriptome, Chinese hamster ovary (CHO) cells with enhanced γ-secretase were compared to cells with abolished γ-secretase activity via a microarray designed for a genetically close species, mouse. Our findings will potentially help to decipher the biology of γ-secretase, including a better understanding of the roles of this enzyme in gene transcription.

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Human T-ALL cell line response to inhibition of Notch signaling

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Human T-ALL cell line response to inhibition of Notch signaling

Project description:Analysis of five Notch signaling-dependent human T-ALL cell lines (ALLSIL, DND41, HPBALL, KOPTK1, TALL-1) treated with gamma-secretase inhibitor (GSI) to block Notch signaling. Samples include parental cells, cells rescued by retroviral transduction with ICN (a GSI-independent form of activated Notch1), and cells retrovirally transduced with c-Myc (an important downstream target of Notch1). Results allow segregation of bona fide Notch targets from other genes affected by gamma-secretase inhibition as well as from targets downstream of c-Myc. Thirty samples were analyzed. Five human T-ALL cell lines (ALLSIL, DND41, HPBALL, KOPTK1, TALL-1) were treated with gamma-secretase inhibitor (1.0 micromolar compound E) vs. DMSO vehicle control for 12 hours. Each cell line was also retrovirally transduced with ICN or c-Myc, FACS sorted, and then treated with GSI vs. DMSO.

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Project description:Notch signaling relies on ligand-induced proteolysis to liberate a nuclear effector that drives cell fate decisions. The location and timing of individual steps required for proteolysis and movement of Notch from membrane to nucleus, however, remain unclear. Here, we use proximity labeling with quantitative multiplexed mass spectrometry to monitor the microenvironment of endogenous Notch2 after ligand stimulation in the presence of a gamma secretase inhibitor and then as a function of time after inhibitor removal. Our studies show that gamma secretase cleavage of Notch2 occurs in an intracellular compartment and that formation of nuclear complexes and recruitment of chromatin-modifying enzymes occurs within 45 minutes of inhibitor washout. This work provides a spatiotemporal map of unprecedented detail tracking the itinerary of Notch from membrane to nucleus after activation and identifies molecular events in signal transmission that are potential targets for modulating Notch signaling activity.

2023-08-02 | PXD042123 | Pride

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