Cell signaling plays a fundamental role in controlling cell growth and differentiation during development. In C. elegans, one of the best understood examples of cell signaling occurs during the induction of the vulva in the hermaphrodite. Vulval development provides an opportunity to study cell signaling in vivo at single cell resolution, since induction is the result of communication between a single regulatory cell (the anchor cell) and a set of six responding cells (the vulval precursor cells). Many genes that function in the vulval cell signaling pathway have already been identified, and most are similar to genes involved in receptor tyrosine kinase pathways in mammals and Drosophila; including let-23 (a receptor tyrosine kinase gene), let-60 (a ras homolog) and mpk-1 (a MAP kinase homolog). This project began when the exciting observation was made that lin-2, a gene required for vulval induction in C. elegans, is similar to membrane- associated guanylate kinase genes (referred to as MAGUK genes) that have previously been identified in Drosophila and mammals. Studies with the C. elegans lin-2 gene provide the first direct evidence that a MAGUK gene interacts with a receptor tyrosine kinase pathway. Other MAGUK proteins may likewise interact with receptor tyrosine kinase pathways in other organisms, and elucidating the role of MAGUK proteins in signal transduction will uncover new steps in this important cell signaling pathway. One of the broad goals of this proposal is to determine how lin-2 functions during vulval cell signaling in C. elegans. Vulval development provides an ideal system for investigating the link between MAGUK proteins and signal transduction, since lin-2 function can be analyzed in the context of a well-characterized tyrosine kinase signaling pathway in which many of the genes have already been identified. By analyzing how lin-2 interacts with these other vulval signaling genes, the step in the signaling cascade that requires lin-2 function will be determined. Furthermore, a combined molecular, genetic and biochemical approach will be used to determine which of the LIN-2 protein domains and predicted enzymatic activities are required for proper cell signaling in vivo. Finally, the interactions between LIN-2 and other proteins involved in the same cellular process as LIN-2 (LIN-7 and LIN-10) will be studied. The proposed investigation of the role of lin-2 and interacting genes during vulval induction is directly relevant to abnormal signaling processes leading to tumor formation. lin-2 is similar to the Drosophila discs-large gene, which functions as a tumor suppressor gene in imaginal disc cells. Our work shows that lin-2 interacts with a highly conserved receptor tyrosine kinase signaling pathway, and constitutive activation of similar pathways in mammalian cells is oncogenic. For example, let-23, sem-5, let-60, lin-45 and lin-31 are """"""""proto-oncogenes"""""""" since they are similar to mammalian receptor tyrosine kinase oncogenes, the crk oncogene, ras, raf and the Qin oncogene, respectively.
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