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. Over-expressed dRet^MEN2 isoforms targeted to the developing retina caused aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRet^MEN2 activated the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRet^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.

Key Words: Drosophila, MEN2, Multiple Endocrine Neoplasia Type 2, Ret, cancer

Online ISS 1091-6490
Copyright 2008 by the Genetics Society of America
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