Notch1

Transmembrane Receptor Oncogene

What is Notch1?

Transmembrane protein involved in a conserved and simple signaling pathway.

What is Notch1?

Transmembrane protein involved in a conserved and simple signaling pathway.

Notch1 has 3 domains

What is Notch1?

Transmembrane protein involved in a conserved and simple signaling pathway.

Notch 1 has 3 domains

Member of the Notch Family (Notch1-Notch4)

What does Notch1 do?

Notch1 plays a role in cell fate determination in many tissues.

e.g. neural and epidermal tissue, hair follicles, dental epithelium.

Essential in T-cell development

Notch1 Signaling Pathway

Ligand Binds to Notch1

Notch1 Signaling Pathway

Ligand Binds to Notch1

Proteases cleave protein on either side of transmembrane domain

Notch1 Signaling Pathway

Ligand Binds to Notch1

Proteases cleave protein on either side of transmembrane domain

Derivative of cytoplasmic domain travels to nucleus as co-activator

Notch1 in Model Organisms

First Discovered in neural development in Drosophila

Also found in mice where overexpression and inactivation experiments were carried out

Notch1 in Mice

Homozygous Notch1 mutants are embryonic lethal at E10.

They are developmentally delayed.

The thymus, where T-cells are formed, is reduced.

Notch1 in Mice

A conditional allele revealed that Notch1 is important at 3 places in Lymphocyte development.

Notch1 is an Oncogene

A chromosomal translocation truncates Notch1 and makes it constitutively active.

This allows the cytoplasmic domain to be cleaved without the binding of a ligand.

This leads to uncontrolled expression of Notch target genes.

Notch1 is an Oncogene

Notch1 mutations are found in up to 50% of T-cell acute lymphoblastic leukemias (T-ALL).

They are also commonly found in cervical and prostate carcinomas as well as some melanomas.

Some cases of T-ALL have mutations in other Notch family members such as Notch3

Possible Breakthroughs

One possible breakthrough is that since the movement of the cytoplasmic domain requires a protease, an inhibitor of this protease could curb constitutive activity.