Binding of scatter factor (SF)/hepatocyte growth factor (HGF) to the c Met receptor tyrosine kinase (RTK) triggers receptor dimerization and phosphorylation on multiple residues within the juxtamembrane, catalytic core and cytoplasmic tail domains, thereby regulating receptor internalization, catalytic activity and multisubstrate docking. c Met contains three tyrosines (Tyr-xx- x-Tyr-Tyr motif) within the activation loop of the catalytic domain. This is also seen with the insulin receptor, insulin-like growth factor receptor (IGF1R) and nerve growth factor (NGF) receptors/Trks, for which phosphorylation of all three tyrosines is required for full activation. With c Met (and the related family member, RON) phosphorylation of Tyr1234 and Tyr1235 have been shown to be important in receptor activation. Activation of the c Met receptor results in binding and/or phosphorylation of many intracellular signaling proteins including multiple adaptor proteins (e.g., Grb2, Shc, Cbl, Crk, cortactin, paxillin, and GAB1), and a variety of other signal transducers (e.g., PI 3-kinase, FAK, Src, ERK1&2, JNK1&2, PLC gamma, and STAT3). Tyr1003 is a negative regulatory phosphorylation site of c Met.