A compendium of ERK targets

Ünal, Elçin; Uhlitz, Florian; Blüthgen, Nils

doi:10.1002/1873-3468.12740

Cited by 153 publications

(128 citation statements)

References 52 publications

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“…The rapid and robust activation of ERK1/2 allows the phosphorylation and modulation of the activity of more than 600 proteins, which are localized either in the cytoplasm or in the nucleus [34-37]. These substrates are important for the regulation of cellular processes such as proliferation, differentiation, migration, and others [4, 38].…”

Section: The Mechanism Of Mapks Translocation Into the Nucleusmentioning

confidence: 99%

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

et al. 2018

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The mitogen-activated protein kinase (MAPK) cascades are central signaling pathways that play a central role in the regulation of most stimulated cellular processes including proliferation, differentiation, stress response and apoptosis. Currently 4 such cascades are known, each termed by its downstream MAPK components: the extracellular signal-regulated kinase 1/2 (ERK1/2), cJun-N-terminal kinase (JNK), p38 and ERK5. One of the hallmarks of these cascades is the stimulated nuclear translocation of their MAPK components using distinct mechanisms. ERK1/2 are shuttled into the nucleus by importin7, JNK and p38 by a dimer of importin3 with either importin9 or importin7, and ERK5 by importin-α/β. Dysregulation of these cascades often results in diseases, including cancer and inflammation, as well as developmental and neurological disorders. Much effort has been invested over the years in developing inhibitors to the MAPK cascades to combat these diseases. Although some inhibitors are already in clinical use or clinical trials, their effects are hampered by development of resistance or adverse side-effects. Recently, our group developed 2 myristoylated peptides: EPE peptide, which inhibits the interaction of ERK1/2 with importin7, and PERY peptide, which prevents JNK/p38 interaction with either importin7 or importin9. These peptides block the nuclear translocation of their corresponding kinases, resulting in prevention of several cancers, while the PERY peptide also inhibits inflammation-induced diseases. These peptides provide a proof of concept for the use of the nuclear translocation of MAPKs as therapeutic targets for cancer and/or inflammation.

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Section: The Mechanism Of Mapks Translocation Into the Nucleusmentioning

confidence: 99%

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

et al. 2018

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“…This regulation by human GSTO1‐1 is of interest as both kinases have many potential downstream targets that are known to have contributions to various cellular processes including survival, growth, proliferation, and metabolism. Akt has more than 100 known substrates and MEK1/2 is the immediate upstream activating kinase of Extracellular signal‐Regulated Kinase 1/2 (ERK1/2) which has 659 direct substrates from a total of 2507 reported downstream targets …”

Section: Resultsmentioning

confidence: 99%

“…Akt has been shown to inhibit stress‐activated MAPK pathways (of which MEK1/2 is a member) to negatively regulate pro‐apoptotic responses, this includes inhibition of ASK1 the upstream activating kinase of JNK and p38, as well as blocking ERK signaling through inhibition of c‐Raf . Akt is also a direct substrate for ERK, the downstream target of MEK1/2, for a feedback loop regulation . Akt is thought to contribute to cell pro‐survival through several downstream targets; for example, the Bcl‐2 family member BAD or the transcription factors FOXO and p53 .…”

Section: Resultsmentioning

confidence: 99%

Glutathione transferase Omega 1‐1 (GSTO1‐1) modulates Akt and MEK1/2 signaling in human neuroblastoma cell SH‐SY5Y

et al. 2019

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In the human neuroblastoma SH‐SY5Y cell line, the glutathione transferase Omega 1‐1 (GSTO1‐1) appears to modulate Akt and MEK1/2 kinase activation. We observed a glutathionylation modification was involved in the activation of Akt but not MEK1/2. With the specific GSTO1‐1 inhibitor ML175, we show the enzyme activity of GSTO1‐1 is important for modulation as the inhibited GSTO1‐1 allowed activation of both Akt and MEK1/2. The inhibition of GSTO1‐1 showed a similar extent of activation of Akt and MEK1/2 as treatment by the endotoxin lipopolysaccharide. The GSTO1‐1 also either directly interacts with Akt and MEK1/2 or interacts with a protein complexed with Akt and MEK1/2 as both kinases coimmunoprecipitated with GSTO1‐1. The results suggest that GSTO1‐1 enzyme activity inhibits the activation of these two kinases to maintain basal levels. The possible regulation by GSTO1‐1 is of interest as both kinases have hundreds of potential downstream targets that are known to have contributions to various cellular processes including survival, growth, proliferation, and metabolism.

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“…Yoon and Segar (Yoon & Seger, 2006), published a comprehensive list of substrates in 2006, but in the past 12 years that list of substrates has grown, due in part through the progress of mass spectrometry techniques that can identify global changes in the phosphoproteome upon activation or inhibition of the ERK pathway. Unal et al (Unal, Uhlitz, & Bluthgen, 2017) have established an online database of substrates to aid investigators in keeping up with the progress of ERK substrate identification. For the remainder of this article, I will discuss how ERKs have been shown to interact with their substrates, techniques that have been used for substrate identification and discuss how ERK phosphorylation of some specific substrates have been shown to regulate cell signaling and cell function.…”

Section: Erk Substratesmentioning

confidence: 99%

Extracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes

Eblen

2018

Advances in Cancer Research

155

104

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The extracellular regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that are involved in regulating cellular signaling in both normal and pathological conditions. Their expression is critical for development and their hyperactivation is a major factor in cancer development and progression. Since their discovery as one of the major signaling mediators activated by mitogens and Ras mutation, we have learned much about their regulation, including their activation, binding partners and substrates. In this review, I will discuss some of what has been discovered about the members of the Ras to ERK pathway, including regulation of their activation by growth factors and cell adhesion pathways. Looking downstream of ERK activation, I will also highlight some of the many ERK substrates that have been discovered, including those involved in feedback regulation, cell migration, and cell cycle progression through the control of transcription, pre-mRNA splicing and protein synthesis.

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A compendium of ERK targets

Cited by 153 publications

References 52 publications

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

Glutathione transferase Omega 1‐1 (GSTO1‐1) modulates Akt and MEK1/2 signaling in human neuroblastoma cell SH‐SY5Y

Extracellular-Regulated Kinases: Signaling From Ras to ERK Substrates to Control Biological Outcomes

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