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Related Concept Videos

Notch Signaling Pathway03:14

Notch Signaling Pathway

6.9K
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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Notch Signaling Pathway03:14

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Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

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Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
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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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Nuclear Localization Signals and Import01:46

Nuclear Localization Signals and Import

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Proteins targeted to the nucleus carry short stretches of amino acid sequences called the nuclear localization signal or NLS. Classical nuclear localization signals are of two types: monopartite and bipartite NLS. Monopartite classical NLS (cNLS) consists of a single cluster of 4-8 amino acids. Bipartite cNLS consists of two clusters of  2-3 amino acids and a 9-12 residue long proline-rich linker bridging the two clusters. Signal clusters are rich in positively charged amino acids such as...
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Nuclear Protein Sorting01:34

Nuclear Protein Sorting

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Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
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Related Experiment Video

Updated: Apr 16, 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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AKT and 14-3-3 regulate Notch4 nuclear localization.

Gopalakrishnan Ramakrishnan1, Gantulga Davaakhuu1, Wen Cheng Chung1

  • 1Cancer Institute, University of Mississippi Medical Center, Jackson, MS 39216.

Scientific Reports
|March 6, 2015
PubMed
Summary
This summary is machine-generated.

The PI3K-AKT pathway negatively regulates Notch4 nuclear signaling by phosphorylating Notch4-intracellular domain (ICD). This phosphorylation by AKT restricts Notch4-ICD to the cytoplasm, impacting gene transcription and cell fate.

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Stimulation of Notch Signaling in Mouse Osteoclast Precursors
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Related Experiment Videos

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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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Heterokaryon Technique for Analysis of Cell Type-specific Localization
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Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Cancer research

Background:

  • Notch receptors regulate cell fate and proliferation.
  • Notch4 is implicated in breast cancer and endocrine resistance.
  • Notch4-intracellular domain (ICD) nuclear translocation regulates gene transcription, but its regulation is unclear.

Purpose of the Study:

  • To investigate the mechanisms regulating Notch4-ICD nuclear localization.
  • To identify and characterize AKT phosphorylation sites on human Notch4-ICD.
  • To elucidate the role of the PI3K-AKT pathway in Notch4 signaling.

Main Methods:

  • Identification of AKT phosphorylation sites on Notch4-ICD.
  • In vitro and in vivo phosphorylation assays.
  • Analysis of growth factor and PI3K inhibitor effects on Notch4-ICD phosphorylation.
  • Investigation of 14-3-3 protein binding to phosphorylated Notch4-ICD.

Main Results:

  • Four distinct AKT phosphorylation sites were identified in human Notch4-ICD.
  • AKT binds and phosphorylates Notch4-ICD in vitro and in vivo.
  • Phosphorylation is growth factor-dependent and PI3K-inhibitor sensitive.
  • Phosphorylation creates 14-3-3 binding sites, sequestering Notch4-ICD in the cytoplasm.

Conclusions:

  • The PI3K-AKT pathway negatively regulates Notch4 nuclear signaling.
  • Phosphorylation of Notch4-ICD by AKT restricts its nuclear translocation.
  • This provides a novel mechanism for controlling Notch4-mediated gene transcription.