Grant: Operating Grant

Receptor Tyrosine Kinases (RTKs) are cell surface proteins that perceive and transmit chemical messages from outside the cells. The relay of RTK signals within the cells is accomplished by distinct proteins complexes that form so-called signaling pathways. One such pathway is known as RAS/MAPK and plays a central role in the control of cell division. Consistent with this, over 30% of all human cancers have mutations in genes encoding factors that directly or indirectly affect this pathway. Therefore, a thorough description of the events governing RAS/MAPK signaling should provide novel targets and strategies for anticancer therapies. RAS governs cell division primarily by sending signals through a module of three core proteins (RAF, MEK and MAPK). The mechanisms and the proteins required for RAS/MAPK function have been remarkably well-conserved during evolution. Therefore, the use of simpler models, such as Drosophila fruit flies, is accelerating the identification and characterization of novel proteins influencing RAS/MAPK signaling. For instance, we have previously identified several new factors required for the RAS/MAPK pathway using genetic screens in Drosophila. One of these is CNK, which we initiated the characterization a few years ago. To our surprise, we found that CNK physically links together several of the keys players composing the RAS/MAPK pathway and therefore appears to work as a molecular scaffold. In this proposal we want to further explore the scaffolding property of CNK. A better understanding of CNK action may lead to the development of drugs that reduce the activity of cancer-causing mutations affecting the RAS/MAPK pathway. Moreover, our preliminary data suggest that CNK influences another pathway, which governs the ability of cells to contact each other or to move around. We now plan to explore this possible new role for CNK, which may shed light on some of the early events leading to cancer cell detachment; a prerequisite for metastasis.