The Notch signaling pathway is a conserved intercellular signaling mechanism that is essential for proper embryonic development in numerous metazoan organisms. Members of the Notch gene family (NOTCHs) encode transmembrane receptors that are critical for various cell fate decisions. Multiple ligands that activate Notch and related receptors have been identified, including Serrate and Delta in Drosophila and JAG1 (MIM.601920) in vertebrates.

Components: Notch1, JAG1 (Jagged1), HES5, MASH1

The Notch signaling pathway is an evolutionarily highly conserved system for cell-cellcommunication, which exists in most if not all multicellular species. NOTCH receptors participate in a signaling pathway that regulates many aspects of morphogenesis in multicellular animals through diverse effects on differentiation, proliferation, and cell survival.

Notch receptors undergo acomplex set of proteolytic processing events in response to ligand activating, which eventuallyleads to release of the intracellular domain of the receptor.Signal transduction is normally initiated by binding to transmembrane ligands of the Serrate or Delta class, which induces proteolytic release of the intracellular NOTCH domain (ICN).

Free ICN translocates to the nucleus to form a short-lived complex with a Rel-like transcription factor, CSL, and Mastermind-like co-activators that activates lineage-specific programs of gene expression.

Thus, the NOTCH pathway provides a means for local environmental cues mediated through cell:cell interactions to direct or antagonize specific developmental programs.

Recent data suggest NOTCH signals control hematopoietic development at multiple decision points through effects on differentiation and self-renewal.

 proteolyctic cleavage by notch receptors by presenilin
 ubiquitination and turnover of the intracellular domain of the Notch receptor

Pathology

In hematopoietic cells

Withdrawal of NOTCH signals at particular decision points leads to hypoplasia of specific lymphoid subsets, whereas enforced NOTCH signaling skews lymphoid development in the opposite direction and causes certain leukemias, including a subset of T-cell acute lymphoblastic leukemias associated with a recurrent t(7;9) translocation involving human NOTCH1.

In central nervous system

Notch signaling is also linked to twoforms of neurodegenerative disease. First, mutations in the Notch 3 receptor leads to the stroke anddementia syndrome CADASIL. Second, proteolytic processing of Notch is controlled by presenilins, which are frequently mutated in Alzheimer's diesase.

References

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