ERK and cell death: cadmium toxicity, sustained ERK activation and cell death

Extracellular signal-related kinase (ERK) is a key player in cell signaling. After 25 years of investigation, ERK has been associated with every major aspect of cell physiology. Cell proliferation, cell transformation, protection against apoptosis, among others, are influenced by ERK function. Surprisingly, ERK has also been associated with two apparently opposing processes. The involvement of ERK in cell proliferation has been extensively described, as well as its function in postmitotic cells undergoing differentiation. The analysis of these apparent discrepancies has led to a more precise understanding of the multiple functions and regulations of ERK. More recently, several groups have identified a new and unexpected role for ERK. Although being accepted as an important player in the protection against cell death by apoptosis, it is now clear that ERK can also be directly linked to cell death signaling. Here, we review the role of ERK in cell response to cadmium and its association with cell toxicity. In this system, ERK is subjected to a continuous activation that can last for days, which ultimately results in cell death. Cadmium entry into cells is responsible for this sustained ERK activation, probably via reactive oxygen species production, and protein kinase C has a negative action on this cadmium-dependent ERK activation by modulating cadmium entry into cells.