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

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.

Pseudomonas aeruginosa infection stimulates mitogen‐activated protein kinases signaling pathway in human megakaryocytes

“…LPS stimulation of A549 lung cells results in binding of importins to NF‐κB and helps in translocation of NF‐κB from the cytoplasm to the nucleus for activation of proinflammatory cytokine genes . Importins have also been shown to be essential for nuclear translocation of MAPK downstream components, including p38, c‐Jun N‐terminal kinases and ERK . On the basis of findings of earlier studies and the present findings, we speculate that importin undergoes a similar mechanism to induce cytotoxicity in P. aeruginosa‐ infected megakaryocytes.…”

“…[35][36][37][38] Importins have also been shown to be essential for nuclear translocation of MAPK downstream components, including p38, c-Jun N-terminal kinases and ERK. 39 On the basis of findings of earlier studies and the present findings, we speculate that importin undergoes a similar mechanism to induce cytotoxicity in P. aeruginosa-infected megakaryocytes. In summary we have here reported the responses of megakaryocytes to P. aeruginosa infection.…”

Beyond Kinase Activity: ERK5 Nucleo-Cytoplasmic Shuttling as a Novel Target for Anticancer Therapy

“…Furthermore, following phosphorylation of the C-terminus, ERK5 may assume an open conformation, exposing the NLS sequence that allows ERK5 nuclear translocation [76,77]. The latter event likely involves Impα/β [78], that transports NLS-containing proteins across the nuclear envelope [79,80]. Finally, a mutated form of ERK5 that cannot be phosphorylated by MEK5 (ERK5-AEF, where TEY has been mutated to AEF) as well as ERK5∆713-AEF are unable to translocate into the nucleus upon stimulation [21,66].…”

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

“…Being responsible for the various distinct and even opposing fundamental cellular processes, the p38 cascade needs to be tightly regulated. Indeed, several regulatory mechanisms that determine the specificity of the cascade have been identified, including the duration and strength of the signals [13,14], which are controlled mainly by dual specificity phosphatases [15,16], scaffold proteins [17], and dynamic subcellular localization of the cascade's components [18]. Importantly, the central roles of the cascade suggest that its dysregulation may cause various diseases.…”