Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer
Abstract
:1. Introduction
2. Epithelial–Mesenchymal Transition
Role of Epithelial–Mesenchymal Transition in Cancer
3. Extracellular-Signal Regulated Kinase: Structure and Function
3.1. Typical Members of the ERK Subfamily
3.1.1. ERK1/2
3.1.2. ERK5
3.2. Atypical Members of the ERK Subfamily
3.2.1. ERK3/4
3.2.2. ERK7/8
4. Signaling Pathways Driving ERK Activation: From Membrane Receptors to Substrates
4.1. Signal Transduction by MAPKs
4.2. Substrates of ERK1/2
4.2.1. Cytosolic Substrates
4.2.2. Nuclear Substrates
4.3. Activation of ERK1/2 Pathway by G Protein-Coupled Receptors
4.4. Regulation of the ERK1/2 Pathway
4.5. Activation of Pathways Dependent on Atypical ERK Members
5. ERK-Activating Mutations in the MAPK Signaling Pathway and Their Contributions to EMT and Cancer Progression
p-ERK as a Marker of Cancer
6. Relationship between ERK and Epithelial–Mesenchymal Transition in Various Cancer Types
6.1. Lung Cancer
6.2. Breast Cancer
6.3. Colorectal Cancer
6.4. Cervical and Ovarian Cancer
6.5. Prostate Cancer
6.6. Other Types of Cancer
7. ERK as a Therapeutic Target in Cancer
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Protein | MAPK Family and Gene Name | UniProtKB Accession ID | Isoform | Length (Amino Acids) | Mass (Da) | Phosphorylation Sites |
---|---|---|---|---|---|---|
ERK1 | MAPK3 | P27361 | Isoform 1 Isoform 2 Isoform 3 | 379 335 357 | 43,136 38,275 40,088 | Thr202/Tyr204 |
ERK2 | MAPK1 | P28482 | Isoform 1 Isoform 2 | 360 316 | 41,390 36,432 | Thr185/Tyr187 |
ERK3 | MAPK6 | Q16659 | – | 721 | 82,681 | Ser186/Gly188 |
ERK4 | MAPK4 | P31152 | – | 587 | 65,922 | Ser189/Gly191 |
ERK5 | MAPK7 | Q13164 | Isoform 1 Isoform 2 Isoform 3 Isoform 4 | 816 677 533 451 | 88,386 73,218 59,328 50,152 | Thr219/Tyr221 |
ERK7/8 | MAPK15 | Q8TD08 | Isoform 1 Isoform 2 Isoform 3 | 544 254 277 | 59,832 28,696 31,112 | Thr175 and Tyr177 |
Inhibitor | Target | Mechanism | Reference |
---|---|---|---|
FR180204 | ERK1/2 | Interacts with the ATP-binding pocket and competes with the nucleotide avoiding the kinase activation | [207] |
SCH772984 | ERK1/2, ERK4 | ATP competitive inhibitor of ERK1/2 preventing the activation of ERK by MEK | [208,209] |
MK-8353 | ERK1/2 | Unknown mechanism | [209,210] |
VTX-11e | ERK2 | Impair the phosphorylation of the kinase’s substrate p90RSK | [207] |
BVD-523 | ERK1/2 | Unknown mechanism | [211] |
“Compound 35” | ERK1/2 | Binds covalently to the ATP-binding pocket preventing the kinase activation | [212] |
SF-3-030 | ERK2 | Inhibits ERK-dependent phosphorylation of ELK1 | [213] |
DEL-22379 | ERK1/2 | Inhibits ERK dimerization without affecting phosphorylation or kinase activity | [207] |
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Olea-Flores, M.; Zuñiga-Eulogio, M.D.; Mendoza-Catalán, M.A.; Rodríguez-Ruiz, H.A.; Castañeda-Saucedo, E.; Ortuño-Pineda, C.; Padilla-Benavides, T.; Navarro-Tito, N. Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer. Int. J. Mol. Sci. 2019, 20, 2885. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20122885
Olea-Flores M, Zuñiga-Eulogio MD, Mendoza-Catalán MA, Rodríguez-Ruiz HA, Castañeda-Saucedo E, Ortuño-Pineda C, Padilla-Benavides T, Navarro-Tito N. Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer. International Journal of Molecular Sciences. 2019; 20(12):2885. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20122885
Chicago/Turabian StyleOlea-Flores, Monserrat, Miriam Daniela Zuñiga-Eulogio, Miguel Angel Mendoza-Catalán, Hugo Alberto Rodríguez-Ruiz, Eduardo Castañeda-Saucedo, Carlos Ortuño-Pineda, Teresita Padilla-Benavides, and Napoleón Navarro-Tito. 2019. "Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial–Mesenchymal Transition in Cancer" International Journal of Molecular Sciences 20, no. 12: 2885. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20122885