Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade

The receptor tyrosine kinase RET functions as the signal transducing recept or for the GDNF (for "glial cell-derived neurotrophic factors") family of l igands. Mutations in the RET gene were implicated in Hirschsprung disease ( HSCR), multiple endocrine neoplasia type 2 (MEN 2), and thyroid carcinomas. In this report we demonstrate that the docking protein FRS2 is tyrosine ph osphorylated by ligand-stimulated and by constitutively activated oncogenic forms of RET. Complex formation between RET and FRS2 is mediated by bindin g of the phosphotyrosine-binding domain of FRS2 to pY1062, a residue in RET that also functions as a binding site for Shc. However, overexpression of FRS2 but not Shc potentiates mitogen-activated protein (MAP) kinase activat ion by RET oncoproteins. We demonstrate that oncogenic RET-PTC proteins are associated with FRS2 constitutively, leading to tyrosine phosphorylation o f FRS2, MAP kinase stimulation, and cell proliferation. However, loss-of-fu nction HSCR-associated RET mutants exhibit impaired FRS2 binding and reduce d MAP kinase activation. These experiments demonstrate that FRS2 couples bo th ligand-regulated and oncogenic forms of RET, with the MAP kinase signali ng cascade as part of the response of RET under normal biological condition s and pathological conditions, such as MEN 2 and papillary thyroid carcinom as.