The KIT receptor has critical roles in several cell systems including hematopoiesis, the pigmentary system, gametogenesis, and in pacemaker cells of the gastrointestinal tract. Normal Kit receptor mediated functions include cell proliferation, cell survival, cell adhesion, cell migration, secretory responses and differentiation. In human neoplasia oncogenic activation of Kit has roles in gastrointestinal stromal tumors, mastocytosis/mast cell leukemia, acute myelogenous leukemia, a minor subset of melanomas and a subset of germ cell tumors. Kit receptor functions are mediated by kinase activation, receptor autophosphorylation and association with various signaling molecules and signaling cascades. How do receptor tyrosine kinases such as Kit mediate distinct cellular responses in different cell types during embryonic development and in the postnatal animal; and what are the requirements for oncogenic transformation in different cell types to produce cancer. We have produced mice containing knock-in point mutations, loss of function and gain of function mutations in the Kit receptor gene in mice which block distinct signaling cascades or which provide for oncogenic activation of Kit in distinct cell types and driving oncogenesis. Most gastrointestinal stromal tumors express the KIT receptor tyrosine kinase, and oncogenic KIT signaling drives GIST tumorigenesis. The principal genetic events responsible for the pathogenesis of GIST are thought to be gain-of-function mutations in the KIT gene or occasionally in the PDGFR alpha gene. Patients with familial GIST syndrome carry a germline KIT gain-of-function mutation. The observation of inherited KIT gain of function mutations in familial GIST provided us with a rationale for developing mouse models for this disease. By using a knock-in strategy, the Kit-V558 deletion mutation found in a familial GIST case was introduced into the mouse genome. Remarkably, heterozygous mutant KitV558 /+ mice provide a faithful mouse model for human familial GIST, and demonstrated that constitutive KIT signaling is necessary and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal (Sommer et al., 2003). These GIST mice provide an excellent tool to study the role of the KIT receptor GIST oncogenesis in vivo and for studies of targeted pharmacological intervention. The overall objective of this proposal is twofold, 1) to continue our investigations into the mechanism of Kit driven GIST oncogenesis and tumor progression, and 2) to investigate new treatment strategies for imatinib sensitive and imatinib resistant GIST.