Genetic Analysis of Intracellular Signaling Crosstalk

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DESCRIPTION (provided by applicant): Overactivation of receptor tyrosine kinases (RTKs) has been linked to many cancers or other human diseases. An important unanswered question is how persistently activated RTK can elicit abnormal cellular responses. Based on our preliminary studies, we propose that an RTK, when overactivated, not only overstimulates its own canonical pathway, but also brings about crosstalk or crossactivation of non-canonical pathways. We use Drosophila, a genetically tractable model organism, to study signaling crosstalk in vivo. Torso (Tor) is a well studied fly RTK most homologous to the mammalian PDGF receptor that signals through the Ras-MAPK pathway. We recently made a surprising discovery that a gain-of-function (GOF) mutant Tor (TorGOF) causes ectopic gene expression patterns via the STAT protein Mrl, encoded by the gene marelle (mrl; a.k.a. DStat92E), and a novel protein TIw, encoded by a gene we named tail low (tlw). Here we propose to investigate the mechanisms of the crosstalk from TorGOF to other signaling pathways by genetic and biochemical means. We will test our hypothesis that at high signaling intensity RTK is able to activate non-canonical pathways that it rarely engages at low signaling intensity or under physiological conditions. In this model, wildtype Tor transduces signals mainly through the Ras/Raf/MEK/MAPK intracellular signaling cassette. TorGOF, however, additionally activates Mrl and possibly Tlw to induce a pathological response. Results from this work should shed light on the mechanisms of signaling crosstalk that may be important for human pathogenesis as well as tumorigenesis.