Integrins are key regulators of gene expression, cell proliferation and migration. Alteration of these processes is central to tumourigenesis. Integrin signals mediate anchorage-dependence of cell growth, while growth of cancer cells is anchorage-independent. Integrins regulate membrane targeting of Rac and Cdc42, also involved in oncogenesis. Integrin-regulated Rac binding sites are in lipid rafts (membrane domains enriched in cholesterol and glycosphingolipids).
Internalisation of Rac binding sites is mediated by caveolin-1, a structural component of a subtype of rafts termed caveolae. Caveolin-1 regulates anchorage-dependent growth and is a tumour suppressor. Integrin-mediated retention of phosphorylated caveolin in focal adhesions inhibits raft internalisation, which occurs upon its recruitment to caveolae after cell detachment. These results may provide a molecular explanation for the role of caveolin-1 as tumour suppressor and provide insight into the mechanism of anchorage-independent growth, one of the hallmarks of cancer.
The main goal of this research proposal is to study the relevance of this novel mechanism to cancer. This specific project aims to identify sequences within caveolin involved in regulation of raft internalisation, cell cycle progression and anchorage-dependent cell growth. Caveolin sporadic mutations occurring in human cancers will be tested for these effects. This objective integrates into a bigger project that also aims to identify molecular mechanisms by which caveolin regulates anchorage-dependent signalling pathways and cell cycle progression and to identify oncogenes that induce constitutive surface localization of rafts (and hence Rac), and/or changes in phosphocaveolin localization.
These studies will contribute to a better understanding of adhesion-dependent signalling and anchorage-dependence of cell growth, and therefore to the pathogenesis of the malignant disease. They will also help in identifying targets for cancer therapy.
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