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

Tubita, Alessandro; Lombardi, Zoe; Tusa, Ignazia; Sbarba, Persio Dello; Rovida, Elisabetta

doi:10.3390/ijms21030938

Cited by 30 publications

(15 citation statements)

References 136 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, and in line with data presented here indicating that SUMOylation is required for ERK5 nuclear translocation, we show that SUMO modification is necessary for ERK5-induced AP-1-mediated proliferation of prostatic adenocarcinoma PC-3 cells (Figure 5B,C). This result is in line with those reporting the relevance of nuclear ERK5 in cancer cell proliferation (reviewed in [36,47]). Expression of key components of the SUMO machinery (such as SUMO1 E1 activating enzyme, E2 conjugation enzyme Ubc9 and some PIAS SUMO E3 ligases) is enhanced in many human cancers, and it correlates with poor prognosis [48].…”

Section: Discussionsupporting

confidence: 92%

SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation

Erazo

Espinosa-Gil

Diéguez-Martínez

et al. 2020

IJMS

View full text Add to dashboard Cite

The MAP kinase ERK5 contains an N-terminal kinase domain and a unique C-terminal tail including a nuclear localization signal and a transcriptional activation domain. ERK5 is activated in response to growth factors and stresses and regulates transcription at the nucleus by either phosphorylation or interaction with transcription factors. MEK5-ERK5 pathway plays an important role regulating cancer cell proliferation and survival. Therefore, it is important to define the precise molecular mechanisms implicated in ERK5 nucleo-cytoplasmic shuttling. We previously described that the molecular chaperone Hsp90 stabilizes and anchors ERK5 at the cytosol and that ERK5 nuclear shuttling requires Hsp90 dissociation. Here, we show that MEK5 or overexpression of Cdc37—mechanisms that increase nuclear ERK5—induced ERK5 Small Ubiquitin-related Modifier (SUMO)-2 modification at residues Lys6/Lys22 in cancer cells. Furthermore, mutation of these SUMO sites abolished the ability of ERK5 to translocate to the nucleus and to promote prostatic cancer PC-3 cell proliferation. We also show that overexpression of the SUMO protease SENP2 completely abolished endogenous ERK5 nuclear localization in response to epidermal growth factor (EGF) stimulation. These results allow us to propose a more precise mechanism: in response to MEK5 activation, ERK5 SUMOylation favors the dissociation of Hsp90 from the complex, allowing ERK5 nuclear shuttling and activation of the transcription.

show abstract

Section: Discussionsupporting

confidence: 92%

SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation

Erazo

Espinosa-Gil

Diéguez-Martínez

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Since its discovery in 1995 [ 5 , 10 ], efforts have been made to explore its physiological role and relevance in disease. Earlier reviews [ 4 , 11 ] published almost a decade ago provided insights into the structural and functional role of ERK5, whereas recent reviews have focused on its contribution to oncogenesis and the perspective of targeting ERK5 in cancer [ 12 , 13 , 14 , 15 , 16 ]. Here, we briefly discuss the current view on the regulation of ERK5 and summarize our knowledge of its role in health and disease.…”

Section: Introductionmentioning

confidence: 99%

The MEK5/ERK5 Pathway in Health and Disease

Paudel

Fusi

Schmidt

2021

IJMS

View full text Add to dashboard Cite

The MEK5/ERK5 mitogen-activated protein kinases (MAPK) cascade is a unique signaling module activated by both mitogens and stress stimuli, including cytokines, fluid shear stress, high osmolarity, and oxidative stress. Physiologically, it is mainly known as a mechanoreceptive pathway in the endothelium, where it transduces the various vasoprotective effects of laminar blood flow. However, it also maintains integrity in other tissues exposed to mechanical stress, including bone, cartilage, and muscle, where it exerts a key function as a survival and differentiation pathway. Beyond its diverse physiological roles, the MEK5/ERK5 pathway has also been implicated in various diseases, including cancer, where it has recently emerged as a major escape route, sustaining tumor cell survival and proliferation under drug stress. In addition, MEK5/ERK5 dysfunction may foster cardiovascular diseases such as atherosclerosis. Here, we highlight the importance of the MEK5/ERK5 pathway in health and disease, focusing on its role as a protective cascade in mechanical stress-exposed healthy tissues and its function as a therapy resistance pathway in cancers. We discuss the perspective of targeting this cascade for cancer treatment and weigh its chances and potential risks when considering its emerging role as a protective stress response pathway.

show abstract

“…The p38 cascade is one of four similar cascades that are all key communication lines between the plasma membranes and the nucleus, and thereby, it is involved in fundamental cellular processes, including stress response, proliferation, differentiation and others [ 1 , 2 , 3 ]. The four MAPK cascades are extracellular signal-regulated kinase (ERK) 1/2 [ 4 ], c-Jun N-terminal kinase (JNK [ 5 ]), p38 [ 6 ], and ERK5 [ 7 ]. The MAPK cascades transmit signals via a sequential activation of protein kinases, which are organized in 3–5 tiers (MAP4K, MAP3K, MAPKK, MAPK, and MAPK activated protein kinases (MAPKAPKs also termed MKs)).…”

Section: Introductionmentioning

confidence: 99%

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

Maik-Rachline

Lifshits

Seger

2020

IJMS

View full text Add to dashboard Cite

The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) cascade is a central signaling pathway that transmits stress and other signals to various intracellular targets in the cytoplasm and nucleus. More than 150 substrates of p38α/β have been identified, and this number is likely to increase. The phosphorylation of these substrates initiates or regulates a large number of cellular processes including transcription, translation, RNA processing and cell cycle progression, as well as degradation and the nuclear translocation of various proteins. Being such a central signaling cascade, its dysregulation is associated with many pathologies, particularly inflammation and cancer. One of the hallmarks of p38α/β signaling is its stimulated nuclear translocation, which occurs shortly after extracellular stimulation. Although p38α/β do not contain nuclear localization or nuclear export signals, they rapidly and robustly translocate to the nucleus, and they are exported back to the cytoplasm within minutes to hours. Here, we describe the physiological and pathological roles of p38α/β phosphorylation, concentrating mainly on the ill-reviewed regulation of p38α/β substrate degradation and nuclear translocation. In addition, we provide information on the p38α/β ′s substrates, concentrating mainly on the nuclear targets and their role in p38α/b functions. Finally, we also provide information on the mechanisms of nuclear p38α/b translocation and its use as a therapeutic target for p38α/β-dependent diseases.

show abstract

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

Cited by 30 publications

References 136 publications

SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation

SUMOylation Is Required for ERK5 Nuclear Translocation and ERK5-Mediated Cancer Cell Proliferation

The MEK5/ERK5 Pathway in Health and Disease

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

Contact Info

Product

Resources

About