RET is a single membrane tyrosine kinase receptor that mediates signaling of GDNF family ligands (GFLs) in association with GFRalpha coreceptors. Aberrant RET signaling results in a number of human diseases and developmental abnormalities, including multiple endocrine neoplasia type 2 syndromes, Hirschsprung disease (intestinal ganglionosis), and developmental abnormalities of the peripheral nervous and urogenital systems in mice. GFL signaling is also important for the survival of neuronal populations such as midbrain dopaminergic neurons and spinal cord motor neurons, which degenerate in Parkinson disease and amyotrophic lateral sclerosis (ALS), respectively. The molecular defects in the signaling pathways that result in the wide variety of RET-mediated abnormalities are largely unknown. This lack of knowledge is an impediment for the creation of rationally designed medical interventions for these conditions. Similar to other receptor tyrosine kinases (RTKs), RET signals through interactions between key phosphotyrosine docking sites and their cognate adaptor proteins. Signals emanating from these interactions are important in RET-mediated regulation of cellular processes such as proliferation, migration, and axonal outgrowth, whereas the perturbation of these processes ultimately leads to diseases. The candidate proposes to characterize mice expressing RET mutants lacking key adaptor docking sites in order to associate these mutations with alterations in key cellular processes that lead to developmental deficits in the peripheral nervous and urogenital systems. As aberrations in RET-stimulated proliferation is central to its role in tumorigenesis and developmental abnormalities, the candidate will utilize engineered fibroblast cell lines to study this aspect of RET biology in further detail. These in vitro assays will be used in conjunction with lentivirus delivery of specific siRNAs to identify signaling components (adaptor proteins) and pathways (MAPK, PLCgamma) that signal through particular RET docking sites to regulate proliferation. The identification of specific components of this signaling pathway will be helpful ultimately in developing targeted therapeutics for these tumors and in enhancing our understanding of nervous system development.
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