Ret is a receptor protein tyrosine kinase that has been implicated in the development of the enteric nervous, endocrine, and renal systems. Mutations associated with multiple endocrine neoplasia types 2A and 2B (MEN 2A and 2B) have been shown to activate the intrinsic kinase and transforming ability of ret (Santoro, M., Carlomagno, F., Romano, A., Bottaro, D. P., Dathan, N. A., Grieco, M., Fusco, A., Vecchio, G., Matoskova, B., Kraus, M. H., and Paolo DiFiore, P. (1995) Science 267, 381-383). Using the cytoplasmic domain of Ret as bait in a yeast two-hybrid screen of a mouse embryonic library, it was discovered that the src homology 2 (SH2) domain containing protein Grb10 bound Ret. Grb10 belongs to an emerging family of SH2 containing adapter proteins, the prototypical member being Grb7. Using glutathione S-transferase fusion proteins, it was demonstrated that the SH2 domain of Grb10 specifically interacted with Ret. Additionally, using an EGFR/Ret chimera, it was shown that Grb10 bound Ret in an activation dependent manner in vivo. This is the first description of a receptor protein tyrosine kinase that utilizes Grb10 as a signaling intermediate.