NOTCH3DR

Investigating a novel role of Notch3 as a dependence receptor and its relevance in vivo

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 Obiettivo del progetto (Objective)

'Cell survival depends on the integration of numerous signals provided by the extracellular environment. Activation of signal transduction by transmembrane receptors is assumed to occur following interaction with a specific ligand. However, some receptors, called dependence receptors (DRs) have been shown to mediate a signal in the absence of ligand. These receptors share the ability to mediate two opposing signals: in the presence of their cognate ligand, they transduce survival signals, whereas, in the absence of their ligand, they induce apoptosis. This idea was initially proposed for the Deleted in Colorectal Cancer (DCC) receptor, and now, number of such receptors has increased over the past ten years. There are now a dozen DRs described including the netrin-1 receptors DCC and UNC5H1-4, RET, TrkC, neogenin, and Patched. Identifying new dependence receptors is an important challenge since it causes a paradigm shift of a specific signalling pathway and alters our understanding of the developmental and physiological processes involving such receptors. For example, the DRs concept revealed a novel role for DCC in colon cancer, for netrin-1 in breast cancer metastasis and angiogenesis. Despite sharing little structural homology, all DRs contain a Dependence Associated Receptor Transmembrane (DART) motif, induce apoptosis in the absence of ligand and are cleaved by caspases to release a pro-apoptotic fragment. Preliminary data shows that Notch3 shares these characteristics. Notch3 is a member of the family of Notch receptors which regulates various stages in development and cancer as the receptors control cellular differentiation, proliferation and death. Notch3 has never been studied as a dependence receptor and the aim of this application is thus to further characterise Notch3 dependence signalling. We will study the mechanisms of Notch3-induced cell death and its relevance in physiological models, the involution of the mammary gland and lung cancers.'

Descrizione progetto (Article)

DRs hold the fate of a cell either by interacting with a ligand to survive or, in the absence of a ligand, when cell death or apoptosis is induced. Not surprisingly, there is a link between the survival function and many cancers, and DRs have therefore become a target for therapeutic strategies. Getting a cell to choose the cell death pathway via a DR is a good way to eliminate the cancer.

The 'Investigating a novel role of Notch3 as a dependence receptor and its relevance in vivo' (Notch3dr) project investigated the newly discovered DR, as in the project name, Notch3.

Project scientists found that overexpression of Notch3 induced apoptosis in a wide range of cancer cells. Evidence of the dual nature of Notch3 occurs when cancer cells expressing Notch3 are cultured with cells expressing ligands. In this situation, cell death does not occur.

From the molecular point of view, the team showed that apoptosis occurs in the presence of caspases, enzymes implicated in the apoptotic pathways. Moreover, caspase-9 is absolutely necessary for Notch3-induced apoptosis. The link appears to be that caspases cleave Notch3 during the induction process; the scientists aim to further test this hypothesis by using mutants without the cleaving caspases.

Specifically looking at the involvement of Notch3 in lung and breast cancer cell lines, the researchers found links between a number of ligands. There were correlations between delta like ligand-4 (Dll-4) and Jagged-2, and Notch3 ligands in lung and breast cancer respectively. Furthermore, Jagged-1 was observed to increase significantly in renal cancer patients and, most importantly, induced cell death when inhibited.

The way forward according to Notch3dr scientists is to induce Notch3 DR activity in cancer cells. Another promising approach is to develop agents that are Notch3 specific therefore reducing toxicity while increasing specificity.