Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRasQ61L)-driven SerpinB2 expression

Ras/extracellular signal-regulated kinase (ERK) signaling is implicated in human cancer development and progression. ERK activation also results in the expression of MAP kinase phosphatases (MKPs) that inactivate ERK. However, it is currently unclear how MKPs regulate the oncogenic potential of the Ras/ERK pathway. Using knockout mice, we identify the MKP encoded by dual-specificity phosphatase 5 (DUSP5) as both a key regulator of nuclear ERK activity and a tumor suppressor in the DMBA/TPA model of Harvey Ras (HRas)-induced skin carcinogenesis. DUSP5 loss results in increased HRas/ERK-inducible SerpinB2 expression, which causes increased skin cancer sensitivity. Our results establish a key role for DUSP5 in the regulation of oncogenic ERK signaling and suggest that this enzyme may play a wider role in tumors containing activated Ras.