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This study was designed to evaluate ERK5 expression in lung cancer and malignant melanoma progression and to ascertain the involvement of ERK5 signaling in lung cancer and melanoma.We show that ERK5 expression is abundant in human lung cancer samples,and ele-vated ERK5 expression in lung cancer was linked to the acquisition of increased metastatic and invasive poten-tial.Importantly,we observed a significant correlation between ERK5 activity and FAK expression and its phosphorylation at the Ser910 site.Mechanistically,ERK5 increased the expression of the transcription factor USF1,which could transcriptionally upregulate FAK expression,resulting in FAK signaling activation to promote cell migration.We also provided evidence that the phosphorylation of FAK at Ser910 was due to ERK5 but not ERK1/2,and we then suggested a role for Ser910 in the control of cell motility.In addition,ERK5 had tar-gets in addition to FAK that regulate epithelial-to-mes-enchymal transition and cell motility in cancer cells.Taken together,our findings uncover a cancer metasta-sis-promoting role for ERK5 and provide the rationale for targeting ERK5 as a potential therapeutic approach.