The ERK Cascade: Distinct Functions within Various Subcellular Organelles

Abstract

The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is a central signaling pathway that regulates a wide variety of stimulated cellular processes, including mainly proliferation, differentiation, and survival, but apoptosis and stress response as well. The ability of this linear cascade to induce so many distinct and even opposing effects after various stimulations raises the question as to how the signaling specificity of the cascade is regulated. Over the past years, several specificity-mediating mechanisms have been elucidated, including temporal regulation, scaffolding interactions, crosstalks with other signaling components, substrate competition, and multiple components in each tier of the cascade. In addition, spatial regulation of various components of the cascade is probably one of the main ways by which signals can be directed to some downstream targets and not to others. In this review, we describe first the components of the ERK1/2 cascade and their mode of regulation by kinases, phosphatases, and scaffold proteins. In the second part, we focus on the role of MEK1/2 and ERK1/2 compartmentalization in the nucleus, mitochondria, endosomes, plasma membrane, cytoskeleton, and Golgi apparatus. We explain that this spatial distribution may direct ERK1/2 signals to regulate the organelles' activities. However, it can also direct the activity of the cascade's components to the outer surface of the organelles in order to bring them to close proximity to specific cytoplasmic targets. We conclude that the dynamic localization of the ERK1/2 cascade components is an important regulatory mechanism in determining the signaling specificity of the cascade, and its understanding should shed a new light on the understanding of many stimulus-dependent processes.

Keywords: ERK; Golgi; MAPK; MEK; mitochondria; nucleus.

Figure 1.

ERK1/2 distribution within the various compartments of the cell. The activation of the ERK1/2 cascade results in a significant translocation of the ERK1/2 molecules to the nucleus, which is mediated by interaction with importin7 to induce mainly proliferation and differentiation. In addition, ERK1/2 translocate into various cellular organelles usually because of interaction with specific scaffold proteins. In each of these organelles, ERK1/2 can either regulate intrinsic activities or direct ERK1/2 signals to nearby cytoplasmic substrates (for details, see text).

Figure 2.

Schematic representation of the different components of the ERK1/2 cascade in resting and mitotic cells. In stimulated cells, most of the ERK cascade outcomes are facilitated by MEK1/2 and ERK1/2. During G2/M phases, some signals are transmitted by MEK1/2 and ERK1/2. In addition, the expression of MEK1 and ERK1 splice variants, MEK1b and ERK1c, is increased. At this stage, the activation of MEK1b and ERK1c is essential for mitotic Golgi fragmentation, while MEK1/2 and ERK1/2 activation induces other mitotic processes.