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 RetMEN2 mutations significantly alter Ret-signaling properties, but
the precise mechanisms by which RetMEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction
pathways required for RetMEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed
dRetMEN2 isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification,
and excessive Ras pathway activation. Genetic analysis indicated that dRetMEN2 acts through the Ras-ERK, Src, and Jun kinase
pathways. A genetic screen for mutations that dominantly suppress or enhance dRetMEN2 phenotypes identified new genes that
are required for the phenotypic outcomes of dRetMEN2 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.
BIOSIS ID
2006.136282
Zoological Record ID
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