Functional analysis of the molecular switch that regulates ADAM10-mediated cleavage of RTK ligands in tumour cells.

Funded Activity Summary

We have determined the structure and identified the region of the ADAM10 metalloprotease that controls its specific cleavage of ephrins. Ephrins and their receptors (Ephs) direct cell positioning during development by controlling cell-cell adhesion and repulsion. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where they are thought to promote aggressive tumours. The switch to cell repulsion occurs by cleavage of the ephrin by ADAM10 which also functions in other cancer promoting events by cleaving growth factors. Our structure reveals how Eph-bound ephrin is specifically targeted by ADAM. We will now determine the relevance of this mechanism for other ADAM10 targets, and design drugs to bind this region and inhibit ADAM function, which we will test in assays measuring tumour cell movement and growth, with the aim of developing therapies to block cancer progression.

Funded Activity Details

Start Date: 01-01-2006

End Date: 01-01-2008

Funding Scheme: NHMRC Project Grants

Funding Amount: $457,267.00

Funder: National Health and Medical Research Council

Research Topics

ANZSRC Field of Research (FoR)

Biochemistry and Cell Biology

ANZSRC Socio-Economic Objective (SEO)

There are no SEO codes available for this funding activity

Other Keywords

ADAM metalloproteases | EGF/EGFR signalling | Eph receptors | cancer therapy | cancer/melanoma | cancer: mechanisms of growth, invasion, metastases | drug design | drug target | drug therapy | protein structure

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