Hepatocyte growth factor (HGF), 1 originally identified and cloned as a mitogenic protein for hepatocytes (1-3), evokes multiple cellular responses, including mitogenesis, morphogenesis, migration, and anti-apoptosis (4 -6). These biological activities of HGF are triggered by tyrosine phosphorylation of c-Met, a specific receptor tyrosine kinase for HGF (7). Biological activities of HGF support tissue organization during development and regeneration of organs, including the liver, kidney, placenta, and skeletal muscle (4 -6), but unregulated and/or constitutive activation of the c-Met receptor endows tumor cells with invasive and metastatic characteristics (8, 9).The c-Met receptor is a heterodimeric protein composed of extracellular ␣-chain and membrane-spanning -chain, which contains an intracellular tyrosine kinase domain. Specific binding of HGF to the c-Met receptor activates tyrosine kinase activity, thereby facilitating phosphorylation of C-terminal tyrosine residues, so-called multifunctional docking sites (10, 11). In addition to the catalytic tyrosine kinase domain, the -chain contains a juxtamembrane domain of 47 amino acid residues, which is highly conserved in distinct species (12). Previous studies indicated that a serine residue at position 985, which resides in the juxtamembrane domain of c-Met, is phosphorylated by treatment of cells with 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator for protein kinase C (PKC). Most interesting, Ser-985 phosphorylation was associated with decreased tyrosine phosphorylation of the c-Met receptor (13); however, neither regulatory mechanisms nor the biological significance of the Ser-985 phosphorylation of c-Met has been elucidated.In the present study, we found that the phosphorylation status of juxtamembrane Ser-985 of the c-Met receptor is bidirectionally regulated through reverse activities of PKC␦/⑀ and protein phosphatase 2A (PP2A), a serine/threonine protein phosphatase. Likewise, oxidative stress in cells induced PKCmediated Ser-985 phosphorylation, and this was associated with inhibition of c-Met tyrosine phosphorylation and subsequent biological responses upon HGF stimulus. Our observations mean that the Ser-985 phosphorylation of c-Met mediated via PKCs and PP2A provides a unique mechanism, which confers cellular responsiveness/unresponsiveness to HGF, depending on the extracellular environment and conditions.