MAPK signalling: ERK5 versus ERK1/2

Abstract

Extracellular-signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family and, similar to ERK1/2, has the Thr-Glu-Tyr (TEY) activation motif. Both ERK5 and ERK1/2 are activated by growth factors and have an important role in the regulation of cell proliferation and cell differentiation. Moreover, both the ERK5 and the ERK1/2 pathways are sensitive to PD98059 and U0126, which are two well-known inhibitors of the ERK pathway. Despite these similarities, recent studies have revealed distinctive features of the ERK5 pathway: ERK5 has a key role in cardiovascular development and neural differentiation; ERK5 nuclear translocation is controlled by its own nuclear localizing and nuclear export activities; and the carboxy-terminal half of ERK5, which follows its kinase catalytic domain, has a unique function.

Figure 1

Two mechanisms to transmit the signal from the cytoplasm to the nucleus in the ERK5 pathway. (A) ERK5 and (B) MEKK2 can translocate from the cytoplasm to the nucleus on stimulation. ERK, extracellular-signal-regulated kinase; MEKK,MAP/ERK kinase kinase.

Figure 2

Molecular mechanisms to control nucleocytoplasmic transport of ERK5 and ERK1/2. (A) ERK5 has a bipartite nuclear localization signal (NLS) in its carboxy-terminal region. In resting cells, the intramolecular interaction between the amino-terminal and the C-terminal halves produces a nuclear export signal (NES) or a domain recognized by cytoplasmic anchor proteins, which has an NES and retains ERK5 in the cytoplasm (not shown). The NES activity might be stronger than the NLS activity. On stimulation, the interaction between the N-terminal and the C-terminal halves is disrupted, and thus the NES activity is abolished. ERK5 then enters the nucleus. (B) By contrast, ERK1/2 contains no NLS or NES. In resting cells, MEK1/2, which has an NES, anchors ERK1/2 in the cytoplasm. On stimulation, ERK1/2 dissociates from MEK1/2 and translocates to the nucleus. ERK, extracellular-signal-regulated kinase; MEK, MAP/ERK kinase.

Figure 3

Hypothetical mechanisms by which ERK5 and ERK1/2 transmit signals to downstream targets. The activating phosphorylation of ERK5 results in the activation of the kinase activity, and ERK5 phosphorylates both downstream target molecules and the carboxy-terminal region of ERK5 itself. The phosphorylated C-terminal region might act as a transcriptional activation activator. Therefore, ERK5 has two mechanisms to transmit signals. By contrast, ERK1/2 might transmit signals only through the phosphorylation of substrates. ERK, extracellular-signal-regulated kinase.