Abstract
The MAP kinase signaling cascade Ras/Raf/MEK/ERK has been involved in a large variety of cellular and physiological processes that are crucial for life. Many pathological situations have been associated to this pathway. More than one isoform has been described at each level of the cascade. In this review we devoted our attention to ERK1 and ERK2, which are the effector kinases of the pathway. Whether ERK1 and ERK2 specify functional differences or are in contrast functionally redundant, constitutes an ongoing debate despite the huge amount of studies performed to date. In this review we compiled data on ERK1 vs. ERK2 gene structures, protein sequences, expression levels, structural and molecular mechanisms of activation and substrate recognition. We have also attempted to perform a rigorous analysis of studies regarding the individual roles of ERK1 and ERK2 by the means of morpholinos, siRNA, and shRNA silencing as well as gene disruption or gene replacement in mice. Finally, we comment on a recent study of gene and protein evolution of ERK isoforms as a distinct approach to address the same question. Our review permits the evaluation of the relevance of published studies in the field especially when measurements of global ERK activation are taken into account. Our analysis favors the hypothesis of ERK1 and ERK2 exhibiting functional redundancy and points to the concept of the global ERK quantity, and not isoform specificity, as being the essential determinant to achieve ERK function.
Highlights
The Ras/Raf/MEK/ERK cascade is a key signaling pathway which integrates extracellular clues from cell surface receptors to gene expression and regulation of multiple cellular proteins
Prior to scrutinizing studies on ERK isoforms functions, we will recap the main traits of ERK1/2 regulation, action and role to aid in understanding the studies on isoform functions
Before the molecular cloning of ERKs by Melanie Cobb’s group (Boulton et al, 1990), ERK1 and ERK2 were known as two proteins respectively p44 and p42 MAPK rapidly phosphorylated in response to all mitogens (Kohno and Pouysségur, 1986; Sturgill et al, 1988)
Summary
The Ras/Raf/MEK/ERK cascade is a key signaling pathway which integrates extracellular clues from cell surface receptors to gene expression and regulation of multiple cellular proteins. ERK cascade plays a crucial role in multiple cellular processes such as cell proliferation, differentiation, adhesion, migration and survival. It is essential for many physiological events including development, immunity, metabolism, and memory formation. The core of this pathway consists in activation of the cascade of three kinases Raf, MEK, and ERK. Prior to scrutinizing studies on ERK isoforms functions, we will recap the main traits of ERK1/2 regulation, action and role to aid in understanding the studies on isoform functions
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