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Protein kinase C-beta II represses hepatocyte growth factor-induced invasion by preventing the association of adapter protein Gab1 and phosphatidylinositol 3-kinase in melanoma cells

Oka, M.; Kikkawa, U.; Nishigori, C.

Journal of Investigative Dermatology 128(1): 188-195

2008


ISSN/ISBN: 0022-202X
Accession: 021615747

The hepatocyte growth factor (HGF) signaling pathway was examined in human normal melanocytes and three malignant melanoma cell lines. HGF-induced activation of c-Met, its receptor-tyrosine kinase, 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 cell lines. The electrophoretic mobility of Gab1, the scaffolding adapter protein that couples activated c-Met and PI3K, was slower in the melanocytes than that in the melanoma cells, and the mobility shifted to that of the melanoma cells after treatment with alkaline phosphatase, indicating that Gab1 is highly phosphorylated on serine and threonine in the melanocytes. Introduction of protein kinase C (PKC)-beta II into the melanoma cells, which is expressed in melanocytes but absent in melanoma cells, resulted in serine and threonine phosphorylation of Gab1 and also prevented tyrosine phosphorylation of Gab1 and its association with PI3K. Furthermore, the introduction of PKC-beta II suppressed HGF-induced activation of PI3K, and attenuated the in vitro invasion activity of the melanoma cells. These results indicate that the HGF signaling process from Gab1 to PI3K is negatively regulated by PKC-beta II, and its loss is critical for melanoma cells to gain invasive potential.

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