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Related Concept Videos

Notch Signaling Pathway03:14

Notch Signaling Pathway

6.3K
The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
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Role Of Notch Signalling In Intestinal Stem Cell Renewal01:12

Role Of Notch Signalling In Intestinal Stem Cell Renewal

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Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
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The Spindle Assembly Checkpoint02:19

The Spindle Assembly Checkpoint

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The spindle assembly checkpoint is a molecular surveillance mechanism ensuring the fidelity of chromosome segregation during anaphase. The checkpoint monitors the completion of all the prerequisite steps before chromosome segregation to determine whether the segregation process should proceed or be delayed.
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
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Regulated Protein Degradation02:58

Regulated Protein Degradation

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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
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Regulated Protein Degradation02:58

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Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

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Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
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Related Experiment Video

Updated: Jan 7, 2026

Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands
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Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands

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A K27-linked Ubiquitin Checkpoint Controls NOTCH Homeostasis.

Behzad Mansoori, Ying Song, Tian Zhang

    Biorxiv : the Preprint Server for Biology
    |December 25, 2025
    PubMed
    Summary
    This summary is machine-generated.

    The autophagy-related protein UVRAG negatively regulates NOTCH1 signaling by recruiting the E3-ligase ITCH, promoting receptor degradation. Restoring UVRAG suppresses NOTCH1-driven cancers.

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    Area of Science:

    • Molecular Biology
    • Cell Biology
    • Cancer Biology

    Background:

    • NOTCH1 signaling is crucial for development but requires tight regulation to prevent pathological activation.
    • Mechanisms preventing excessive NOTCH1 activation remain largely unknown.
    • Dysregulated NOTCH1 signaling drives various cancers, including T-cell leukemia.

    Purpose of the Study:

    • To identify novel regulators of NOTCH1 signaling that prevent its uncontrolled activation.
    • To elucidate the molecular mechanisms by which NOTCH1 activity is curtailed.
    • To explore the therapeutic potential of targeting NOTCH1 regulation in cancer.

    Main Methods:

    • Identified UVRAG as a negative regulator of NOTCH1 using cellular assays.
    • Investigated the interaction between UVRAG, ITCH, and NOTCH1.
    • Utilized ubiquitination assays to detect K27-linked ubiquitination of NOTCH1.
    • Examined the role of the UVRAG-ITCH-ESCRT axis in T-cell leukemia models.

    Main Results:

    • UVRAG recruits and activates the E3-ligase ITCH upon NOTCH1 activation.
    • ITCH catalyzes K27-linked ubiquitination of membrane-tethered NOTCH1, targeting it for ESCRT-dependent lysosomal degradation.
    • Disruption of the UVRAG-ITCH-ESCRT pathway leads to stabilization of NOTCH1 intermediates and amplified oncogenic signaling.
    • Restoring UVRAG in T-cell leukemia models reduced NOTCH1 activity, suppressed disease progression, and enhanced therapeutic response.

    Conclusions:

    • UVRAG acts as a critical negative regulator of NOTCH1 signaling through a ubiquitin-dependent degradation pathway.
    • The UVRAG-ITCH-ESCRT axis represents a safeguard circuit for maintaining NOTCH1 signaling homeostasis.
    • Targeting this axis offers a potential therapeutic strategy for NOTCH1-driven cancers.