A drosophila model of multiple endocrine neoplasia type 2

Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that Ret(MEN2) Mutations significantly alter Ret-signaling properties, but the precise mechanisms by which Ret(MEN2) promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for Ret(MEN2) activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRet(MEN2) isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRet(MEN2) acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance EdRet(MEN2) phenotypes identified new genes that are required for the phenotypic outcomes of dRet(MEN2) activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis.