How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer?

Abstract

Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) are members of the mitogen-activated protein kinase super family that can mediate cell proliferation and apoptosis. The Ras-Raf-MEK-ERK signaling cascade controlling cell proliferation has been well studied but the mechanisms involved in ERK1/2-mediated cell death are largely unknown. This review focuses on recent papers that define ERK1/2 translocation to the nucleus and the proteins involved in the cytosolic retention of activated ERK1/2. Cytosolic retention of ERK1/2 denies access to the transcription factor substrates that are responsible for the mitogenic response. In addition, cytosolic ERK1/2, besides inhibiting survival and proliferative signals in the nucleus, potentiates the catalytic activity of some proapoptotic proteins such as DAP kinase in the cytoplasm. Studies that further define the function of cytosolic ERK1/2 and its cytosolic substrates that enhance cell death will be essential to harness this pathway for developing effective treatments for cancer and chronic inflammatory diseases.

Figure 1. Mechanism of ERK activation and cell proliferation

Activation of receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCRs) by growth factors or mitogens leads to the recruitment of an adaptor protein Grb2 (growth factor receptor bound protein) and the guanine nucleotide exchange factor (SOS). The SOS activates Ras to recruit and activate Raf at the plasma membrane by phosphorylation at multiple sites. MEK1/2 is which then phosphorylated at two serine residues that subsequently phosphorylates ERK1/2 on both threonine and tyrosine. Activated ERK1/2 phosphorylates RSK and both RSK and ERK translocate to the nucleus where they activates multiple transcription factors ultimately resulting in effector protein synthesis and causing changes in cell proliferation and survival. ERK phosphorylation of MEK and possibly Raf can inactivate the pathway at those steps creating a negative feedback loop.

Figure 2. Mechanisms of ERK1/2-mediated oncogenesis

ERK1/2 activation promotes metaplasia and tumor development by phosphorylating Bim and Bid and causing the proteosomal degradation of Bim and the sequestration of Bad to the phosphoserine-binding proteins and, thereby, inhibiting apoptosis. In a separate pathway, ERK1/2 activation phosphorylates FOXO3a at Ser 294, Ser 344, and Ser 425 and facilitates FOXO3a-MDM2 interaction. This interaction enhances FOXO3a degradation through a MDM2-dependent ubiquitin-proteosome pathway, leading to tumor development.

Figure 3. Mechanism of ERK1/2-mediated cell death

The cytoplasmic of ERK1/2 by Bik, PEA-15 or DAPK plays a major role in ERK1/2-mediated cell death. Activated ERK1/2 interacts with PEA-15, Bik, and DAPK and is sequestered in the cytoplasm. Inhibition of ERK1/2 nuclear localization impairs ERK1/2-mediated survival signals and in addition augments the proapoptotic signals of DAPK by phosphorylating the cytoplasmic DAPK.