RET RECEPTOR TYROSINE KINASE ACTIVATES EXTRACELLULAR SIGNAL-REGULATEDKINASE-2 IN SK-N-MC CELLS

Ret is a receptor tyrosine kinase predominantly expressed in tissue de rived from the neuroectoderm and is involved in multiple endocrine neo plasia type 2A and 2B, familiar medullary thyroid carcinoma, and Hirsc hsprung's disease, The ligand for the receptor is still unknown, Previ ously, using a human epidermal growth factor receptor - Ret chimaeric receptor (HERRet) stably transfected into fibroblasts, it was shown th at Pet 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 r eport we describe early signaling events induced by the activated HERR et fusion receptor in a cell line derived from neuroectodermal tissue, SK-N-MC, In these cells, activated HERRet induces tyrosine phosphoryl ation of She, complex formation of She with Grb2 and Sos and activatio n 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 p21ras(asn17) mutant, showing that activation of ER K2 is mediated by p21ras, These results suggest that Pet can induce ER K2 activation in a p21ras dependent manner in cells derived from tissu e where Pet is endogenously expressed.