The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic
Karen Flores1, Suresh Singh Yadav1, Arieh A Katz2
1Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
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.
Insights
New peptides block mitogen-activated protein kinase (MAPK) nuclear import, preventing cancer and inflammation. These findings highlight MAPK nuclear translocation as a promising therapeutic target for disease treatment.
Area of Science:
- Cellular signaling and molecular biology
- Molecular mechanisms of cancer and inflammation
Background:
- Mitogen-activated protein kinase (MAPK) cascades regulate crucial cellular processes like proliferation, differentiation, and apoptosis.
- Four major MAPK cascades exist: ERK1/2, JNK, p38, and ERK5, each with distinct nuclear translocation mechanisms involving importins.
- Dysregulation of MAPK pathways is implicated in diseases such as cancer and inflammation.
Purpose of the Study:
- To investigate the potential of targeting MAPK nuclear translocation as a therapeutic strategy.
- To develop novel peptide inhibitors that block specific MAPK-importin interactions.
Main Methods:
- Development of two myristoylated peptides: EPE peptide targeting ERK1/2-importin7 interaction and PERY peptide targeting JNK/p38-importin interactions.
- Assessment of the peptides' ability to inhibit nuclear translocation of their respective MAPKs.
- Evaluation of the therapeutic efficacy of these peptides in preventing cancer and inflammation.
Main Results:
- EPE peptide successfully inhibited ERK1/2 nuclear translocation, leading to the prevention of several cancers.
- PERY peptide blocked JNK/p38 nuclear translocation, demonstrating efficacy in preventing both cancer and inflammation-induced diseases.
- These peptides demonstrated a proof-of-concept for targeting MAPK nuclear import.
Conclusions:
- Inhibiting MAPK nuclear translocation is a viable therapeutic approach for treating cancer and inflammatory conditions.
- The developed EPE and PERY peptides represent promising novel therapeutic agents.
- Targeting importin interactions offers a new avenue for drug development in oncology and immunology.
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