Role of β isoform of protein kinase C in hepatocyte growth factor-induced signal transduction in pigment cells

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The signaling pathway of hepatocyte growth factor (HGF) through its receptor-tyrosine kinase c-Met was examined in human normal melanocytes and malignant melanoma cell lines. HGF-induced c-Met activation was observed in both melanocytes and melanoma cells, whereas phosphatidylinositol 3-kinase (PI3K), a downstream target of c-Met, was not activated in the melanocytes but enhanced in the melanoma cells. Therefore, the role of Gab1, the scaffolding adapter protein that couples activated c-Met and PI3K, was analyzed in these cells. Gab1 in the melanocytes showed an electrophoretic mobility slower than that of the melanoma cells, and the mobility shifted to that of the melanoma cells after the treatment with alkaline phosphatase, indicating that Gab1 is highly phosphorylated on serine and threonine in the melanocytes. Introuction of protein kinase C (PKC) βII in the melanoma cells using adenovirus vector, that is expressed in the melanocytes but is absent in the melanoma cells, resulted in serine and threonine phosphorylation of Gab1. Furthermore, the introduction of PKCβII suppressed HGF-induced activation of Pl3K. These results indicate that the HGF signaling process from Gab1 to PI3K is negatively regulated by PKCβII.