Notch1 signaling

 

The Notch signaling pathway is evolutionarily conserved and the basic molecular players in this pathway are ligands (Delta and Jagged), Notch receptors, and the transcription factors. Notch is a transmembrane heterodimeric receptor and there are four distinct members (Notch1 to Notch4) in humans and rodents.

 

 

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Notch1 signaling

1.     Notch receptors are heterodimeric proteins that synthesized as single-chain precusors and cleaved into an extracellular and a transmembrane subunit by a furin-like protase in the trans-Golgi. (S1)

2.     Physical interactions between specific EGF repeats of the ligand and Notch then trigger the second cleavage of Notch, which releases the majority of the extracellular domain. (S2)

3.     Truncated Notch is then a substrate for γ-secretase, a multicomponent complex that cleaves Notch within its transmembrane domain and releases its intracellular domain. (S3)

 

Function

²  Cell fate determination, proliferation and apoptosis

²  Differentiation – T cell, Muscle cell, Neuronal cell

²  Cell death, Cell survival

²  Cancer

²  Neurodegenerative Disease

 

 

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A.    Gate-keeper function: Notch maintains stem and/or transient amplifying cells (TA) in an undifferentiated state. In the intestine for example, Notch prevents crypt progenitor cells (TA) from differentiating.

B.     Binary cell fate decisions: In the lymphoid system Notch specifies the T cell lineage at the expense of the B cell lineage from an (at least) bi-potent early thymocyte progenitor.

C.     Induction of differentiation: In the skin, Notch induces terminal differentiation events of TA cells, and during thymocyte differentiation Notch1 promotes differentiation of proTcells into preT cells.

D.    Tumorigenesis: Overexpression of Notch within hematopoietic bone marrow cells or in T cell progenitors results in T cell leukemias, and as such, Notch functions as an oncogene. However in the skin, Notch functions as a tumor suppressor since loss of Notch signaling results in the development of basal cell carcinoma-like tumors.