Coupling met to specific pathways results in distinct developmental outcomes

Receptor tyrosine kinases (RTKs) mediate distinct biological responses by s timulating similar intracellular signaling pathways. Whether the specificit y of the response is determined by qualitative or quantitative differences in signaling output is not known. We addressed this question in vivo by rep lacing the multifunctional docking sites of Met, the receptor for hepatocyt e growth factor, with specific binding motifs for phosphatidylinositol-3 ki nase, Src tyrosine kinase, or Grb2 (Met(2P), Met(2S), and Met(2G), respecti vely). All three mutants retained normal signaling through the multiadaptor Gab1, but differentially recruited specific effecters. While Met2G mice de veloped normally, Met2P and Met(2S) mice were loss-of-function mutants disp laying different phenotypes and rescue of distinct tissues. These data indi cate that RTK-mediated activation of specific signaling pathways is require d to fulfill cell-specific functions in vivo.