ADAM10 as a gatekeeper of receptor tyrosine kinase activation and trafficking: comparative analysis of cell-morphogenetic and mitogenic Eph and EGF receptor signalling pathways

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Eph and EGFR receptor tyrosine kinases are key mediators of cell-cell communication, with important roles in normal development and oncogenic transformation. Amongst other functions, they control cell positioning by directing migrating cells. Signalling by Eph and EGFR, amongst other RTKs, is regulated by transmembrane zinc metalloproteases of the ADAM family. ADAM proteolysis releases Eph/ephrin-mediated cell contacts during cell-cell repulsion and shedding of EGFR ligands is a prerequisite for EGFR activation. We propose that ADAMs are gatekeepers for these signalling pathways. Recent findings indicate that shedding may be controlled both through recognition by ADAM of an intact receptor/ligand complex and by the activity and conformation of the RTK cytoplasmic domain. The proposed studies will examine the fate of Eph and EGFR signalling complexes in the context of ADAM-mediated ligand cleavage and subsequent receptor-mediated endocytosis. We propose a comprehensive survey of ADAM-controlled Eph and EGF receptor signalling pathways, in particular those continuing during endocytosis, is essential for achieving a more complete understanding of cell-cell communication mechanisms. In the context of tumour biology, these new insights into ADAMcontrolled RTK signalling will aid development or optimisation of therapeutic approaches targeting de-regulated RTK function.