Ret is a receptor tyrosine kinase predominantly expressed in tissue derived from the neuroectoderm and is involved in multiple endocrine neoplasia type 2A and 2B, familiar medullary thyroid carcinoma, and Hirschsprung's disease. The ligand for the receptor is still unknown. Previously, using a human epidermal growth factor receptor - Ret chimaeric receptor (HERRet) stably transfected into fibroblasts, it was shown that Ret activation induces the activation of p21ras, but, surprisingly, activation of extracellular signal-regulated kinase 2 (ERK2) was not observed (Santoro et al. (1994) Mol. Cell. Biol., 14, 663). In this report we describe early signaling events induced by the activated HERRet fusion receptor in a cell line derived from neuroectodermal tissue, SK-N-MC. In these cells, activated HERRet induces tyrosine phosphorylation of Shc, complex formation of Shc with Grb2 and Sos and activation of p21ras. Importantly, also ERK2 is activated. This activation was strong and sustained for at least 2 h. Activation was abolished by the dominant negative p21rasasn17 mutant, showing that activation of ERK2 is mediated by p21ras. These results suggest that Ret can induce ERK2 activation in a p21ras dependent manner in cells derived from tissue where Ret is endogenously expressed.