Cooperative function of oncogenic MAPK signaling and the loss of Pten for melanoma migration through the formation of lamellipodia.

The combination of oncogenes and tumor suppressors is involved in cancer development; however, it is still unknown whether their combination plays a critical role in cancer metastasis. We herein investigated whether genetic combinations affected cell migration ability by establishing the immortalized melanocytes, melan-a cells, with an oncogene, either BRAF or GNA11, and the loss of mouse Pten. The loss of mouse Pten or human PTEN increased the cell migration ability of our established cells and human melanoma cell lines with oncogenic MAPK signaling and the BRAF or NRAS background, but not with the GNA11 background or no oncogenes. Although increased migration was not related to PI3K-AKT activation, those migration is regulated by the induction of some components in the WAVE regulatory complex, resulting in a higher rate of the formation of lamellipodia. On the other hand, BRAF induced EphA2 phosphorylation at serine 897 through RSK and was also required for cell migration and the formation of lamellipodia. Therefore, the oncogenic MAPK pathway and loss of Pten in melanoma were important for cell migration through the formation of lamellipodia, suggesting the significance of an appropriate combination of genetic alterations not only in cancer development, but also cancer metastasis.