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.

Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

“…numerous cellular and developmental processes. 18,19 The somatic mutations we identified cluster within or adjacent to the protein's negative regulatory domain ( Figure 2); they have been observed in neoplasms, including melanoma, lung cancer, and hematopoietic malignancies, [20][21][22][23][24][25] and have been shown to constitutively increase MEK1 activity. [26][27][28] MEK1 and its paralog MEK2 phosphorylate ERK1 and ERK2.…”

“…MAPK signaling is activated by receptor tyrosine kinases, integrins, and G protein coupled receptors and is modulated by cross-talk with several other signaling pathways including the AKT-mTOR pathway. 19 Somatic mutations affecting proteins upstream of MEK1 occur in cancer and other types of vascular malformations. 12,19,[29][30][31][32][33][34] The MAP2K1 mutations we detected in AVMs likely alter the function of MEK1 by producing a hypermorphic or neomorphic effect, since these mutations have previously been shown to increase ERK1 and ERK2 phosphorylation in tumors and in cultured cells.…”

Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth

“…7k) suggesting that RelB is a direct substrate for the kinase ERK1. Active ERK is known to regulate transcription factors in the nucleus 45 and we detected significant amounts of nuclear phospho-ERK1 in MM cells (Supplementary Fig. 7f).…”

Le rôle des kinasesMek1etMek2dans la formation de la barrière hématoplacentaire chez la souris

“…L'ensemble de ces données souligne le rôle crucial de la voie ERK/MAPK dans la formation des structures extraembryonnaires. < cibles intracellulaires localisées dans la membrane plasmique, le cytoplasme, le cytosquelette ou le noyau [1,2]. Plusieurs cascades de signalisation MAPK ont été décrites chez les vertébrés.…”

“…Vers le 8,5 e jour de gestation, il y a liaison du mésoderme allantoïde -qui est à l'origine l'importance de la voie dans un grand nombre de processus cellulaires [2,6]. Le rôle de la voie ERK/MAPK lors du développement placentaire a été largement démontré chez la souris par la caractérisation de mutants pour des gènes associés à l'activation de la voie.…”