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Characterisation of mutant MET oncogenes

There is increasing evidence to support the concept that the malignant behavior of some tumors is sustained by the deregulated activation of growth factor receptors. Our work in the past few years has uncovered an important regulator of invasive cell growth, the Met receptor tyrosine kinase. In normal cells, Met acts to relay signals from the cell surface that promote tissue organisation. However when these pathways are altered in cancer cells, this acts to enhance cell invasion the first step of metastasis.

Our aims are to identify what signal transduction pathways are important for the development of human cancers and how these can be targeted with drug therapies. This is a complex question that requires a full understanding of how signals are integrated in normal cells and how these signals become altered in tumor cells, in the context of other genetic alterations.

My lab has focused on and will continue to address these questions using the Met receptor tyrosine kinase and oncogene as a model. We will focus on signals required for anchorage independent growth, morphological cell transformation, epithelial mesenchymal transition, cell invasion and tumorigenesis.

1. Mechanisms of activation and cell transformation by receptor tyrosine kinases
Deregulation of receptor tyrosine kinases in human cancers can occur through positive activation of the receptor or through the loss of negative regulatory controls. We have identified that Cbl a ubiquitin ligase acts as a negative regulatory signal for the Met receptor. We will establish the molecular mechanism through which Cbl negatively regulates the Met receptor and establish if this is a mechanism for receptor deregulation in human cancers. We will exploit the use of substrate specific variants of the Met receptor to dissect signaling pathways essential for tumor induction and metastasis and will dissect signals that promote tumor angiogenesis.

2. Role of Gab Family Signal Amplifiers in Epithelial Morphogenesis and tumorigenesis
Tight control of cell proliferation and morphogenesis is required to ensure normal tissue patterning and prevent cancer. Our objectives are to understand how Gab family docking proteins modulate epithelial morphogenesis by addressing; i) which Gab1 dependent signals are required for morphogenesis, by assessing known Gab1 associated proteins and Gab1 associated proteins identifid by tandem mass spectroscopy, ii) the molecular basis through which the tyrosine phosphatase SHP-2 is required for morphogenesis.

3. Signals Regulating Epithelial Cell Motility and Invasion in Breast Cancer
We will continue to identify key regulators of epithelial cell motility and invasion. We will establish the molecular basis through which the Crk adapter protein induces epithelial cell migration using a proteomic approach to identify Crk associated proteins and using cell biology and mouse models for cell invasion. A microarray approach will be used to identify genes associated with breast cancer progression and cell biology and animal models will be used to understand the function of such genes.