Posted on 10/29/2011 10:23:33 PM PDT by neverdem
Sci. Signal., 25 October 2011
Vol. 4, Issue 196, p. eg9
[DOI: 10.1126/scisignal.2002601]
Nancy R. Gough1*
1 Editor of Science Signaling, American Association for the Advancement of Science, 1200 New York Avenue, N.W., Washington, DC 20005, USA.
Abstract: The extracellular signal–regulated kinase (ERK) pathway is one of the superfamily of mitogen-activated protein kinase pathways. Signals transmitted by this kinase cascade activate a pair of related proteins, ERK1 and ERK2. Research published in Science Signaling shows that, despite the wealth of knowledge about this pathway, previously unknown functions continue to be discovered and additional components in this pathway continue to be identified. Thus, we are continuing to learn the plays and recruit the players in the game that is ERK signaling.
One might expect that the functions and constituents of a pathway as extensively studied as the extracellular signal–regulated kinase (ERK) pathway would be complete. A text search of PubMed for "ERK" returns more than 20,000 results. However, this issue of Science Signaling and research published or highlighted in the journal in the past year suggest that there are discoveries still to be made for this pathway. The ERK pathway is one of a superfamily of mitogen-activated protein kinase (MAPK) cascades. The ERK cascade results in the activation of two related proteins ERK1 and ERK2, and this pathway is commonly activated by various cell-surface receptors, such as receptor tyrosine kinases, G protein–coupled receptors, and adhesion receptors.
Signaling through this pathway involves a three-step kinase cascade activated by small guanosine triphosphatases (GTPases) of the Ras family (see the Connections Map by Johnson). Ras is typically recruited to cell-surface receptors by adaptor proteins and then it is activated, enabling it to stimulate the first kinase in the cascade, a member of the Raf family of mitogen-activated protein kinase kinase kinases (MAPKKKs). Raf, in turn, phosphorylates and activates its target MAPKK, a member of the MEK (also known as MKK) family. As are all MAPKKs, the MEKs are dual-specificity kinases that phosphorylate both threonine and tyrosine residues in their targets, ERK1 and ERK2. Phosphorylation of ERK1 and ERK2 activates their catalytic activity and changes their affinity for binding partners, resulting in their dynamic redistribution to the nucleus, and connecting cell-surface receptors to changes in gene expression.
One of the best-known functions of the ERK pathway is the promotion of proliferation and differentiation. Exactly how the same pathway can produce these two outcomes has been the subject of intense investigation. Andreu-Pérez et al. provided a piece to that puzzle when they reported that posttranslational modification of Raf by methylation influenced Raf stability and, thus, the amplitude and duration of ERK signaling, which affected the cellular response of differentiation or proliferation.
Understanding the specificity of the cellular response would be aided by a better understanding of the specific functions of ERK1 and ERK2. However, this is hampered by the fact that they are both recognized by the same antibodies and are typically both activated in response to a particular stimulus. In a Research Resource, Carlson et al. combined mass spectrometric analysis with chemical genetics to identify specific substrates of ERK2. The 80 targets that they found were associated with diverse cellular processes, including regulation of transcription and translation, messenger RNA (mRNA) processing, and activity of the Rho family of GTPases. The Review by Rodríguez and Crespo focused on functions of ERK2 that do not rely on its kinase activity. It appears that kinase-independent interactions with ERKs are sufficient to influence protein function and gene expression.
ERKs are well known as regulators of gene expression. Indeed, one of the targets identified by Carlson et al. for ERK2 was the transcriptional repressor ETV3, which exhibited reduced DNA binding when phosphorylated by ERK2. In a Research Article from the Archives, Yasuda et al. reported a transcriptional regulatory function for the ERKs in the differentiation of B cells. Although well known for their roles in regulating transcription factor activity and gene expression, ERKs are also becoming recognized for regulating cytosolic processes, including cellular metabolism, as highlighted in the Editors’ Choice by VanHook.
Another approach to identifying pathway components and regulators is the application of high-throughput genomic and proteomic analyses as done by Friedman et al. in a Research Resource in this issue and by Vinayagam et al. in a Research Resource from the 6 September 2011 issue. These complementary studies identified previously unknown regulators and dynamics of the ERK pathway in humans (Vinayagam et al.) and in the model organism, the fruit fly Drosophila melanogaster (Friedman et al.). Vinayagam et al. created a large protein-protein interaction network and then applied a computational approach to assign direction to the interactions among the proteins. With the resulting directed network, they evaluated growth factor–induced protein phosphorylation dynamics and uncovered previously unknown modulators of the ERK pathway. Friedman et al. combined protein-protein interaction screens with RNA interference (RNAi) functional genomic screens in Drosophila cell lines to identify components of the ERK pathway downstream of two receptor tyrosine kinases. Their analysis suggested that these receptors may compete for some common components, in addition to using receptor-specific and cell-specific signal transduction pathways. As Friedman et al. emphasize, understanding the ERK pathway is clinically relevant because aberrant signaling through this pathway is associated with many human diseases and developmental disorders.
Exploration of the ERK pathway for understanding or treatment of human disease was the topic of research in the Archives. Little et al. and Corcoran et al. identified a mechanism by which cancer cells become resistant to drugs that target the ERK pathway. Lau et al. explored signaling in response to the inflammatory cytokine tumor necrosis factor–α (TNF-α) in the intestine, which has implications for inflammatory bowel disease, and found that the ERK pathway was a critical mediator of TNF-α. Computational approaches to studying the ERK pathway have also yielded insight of clinical importance as exemplified by the work of Sturm et al., which suggested that the most effective clinical targets may be outside the part of the pathway exhibiting the properties of a negative feedback amplifier
The studies highlighted here show that diverse approaches, from proteomic and genomic analysis to computational biology to cell biological and biochemical analyses, continue to provide insight into the ERK pathway. Research Resources, especially, provide additional leads for investigating pathway functions, pathway crosstalk, and regulatory interactions, which should produce deeper understanding of this clinically relevant pathway.
* Corresponding author. E-mail, ngough{at}aaas.org
Citation: N. R. Gough, Focus Issue: Recruiting Players for a Game of ERK. Sci. Signal. 4, eg9 (2011).
MAPK Signaling
Proteomic and Functional Genomic Landscape of Receptor Tyrosine Kinase and Ras to Extracellular Signal–Regulated Kinase Signaling
Sci. Signal. 4 (196), rs10. [DOI: 10.1126/scisignal.2002029]
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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882
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immunology ping
Evrey Sunday afternoon, Mom and Dad and me and my sister would sit down for a good game of ERK. Mom would make lemonade in the summer and hot chocolate in the winter. During the fall and spring, we’d each drink a quart of whiskey. ERK - It’s for everyone!
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