ERK5 Is a Critical Mediator of Inflammation-Driven Cancer

Finegan, Katherine G.; Perez-Madrigal, Diana; Hitchin, James R.; Davies, Clare C.; Jordan, Allan M.; Tournier, Cathy

doi:10.1158/0008-5472.can-13-3043

Cited by 55 publications

(67 citation statements)

References 36 publications

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“…ERK5 has been recently studied as a target for mediating inflammation (23,24,26). We determined the activity of the ERK5 compounds in cellular assays of inflammatory response.…”

Section: Resultsmentioning

confidence: 99%

“…Effects of this inhibitor on cell proliferation were shown to be comparable to overexpression of a dominant negative ERK5 mutant (20,21) or to siRNA-mediated ERK5 knockdown (21,22), implicating a key role of the kinase function. Multiple reports have shown promising and corroborating effects of ERK5 knockdown and pharmacological inhibition in controlling inflammation and tumor growth (20,(22)(23)(24)(25)(26).Given the proposed therapeutic uses for ERK5 inhibitors, we set out to develop improved compounds with high selectivity and potency. With these ERK5 compounds, we show that first-generation ERK5 inhibitors actually derived the bulk of their biological activity from off-target activity on bromodomains (BRDs).…”

mentioning

confidence: 99%

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ERK5 kinase activity is dispensable for cellular immune response and proliferation

Lin¹,

Amantea²,

Nomanbhoy³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal, and tissue-restricted deletions have profound effects on erythroid development, cardiac function, and neurogenesis. In addition, depletion of ERK5 is antiinflammatory and antitumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no antiinflammatory or antiproliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains, conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a noncatalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity and delineate which can be pharmacologically targeted.) is a member of the mitogen-activated protein kinase (MAPK) family, which includes ERK1/2, JNK1/2/3, and p38α/β/δ/γ (1). However, unlike the other MAPK members, ERK5 contains a unique 400-amino-acid C-terminal domain in addition to the kinase domain. Through the MAPK signaling cascade, mitogenactivated protein kinase kinase 5 (MEK5) activates ERK5 by phosphorylating the TEY motif in the N-terminal activation loop (2). This event unlocks the N-and C-terminal halves, allowing ERK5 to auto-phosphorylate multiple sites in its C-terminal region, which can then regulate nuclear shuttling and gene transcription (3, 4). Noncanonical pathways (including cyclin-dependent kinases during mitosis and ERK1/2 during growth factor stimulation) also exist for phosphorylation of sites in the ERK5 tail (5-7). Although ERK5 has been demonstrated to directly phosphorylate transcription factors (8-10), the noncatalytic C-terminal tail of ERK5 can also interact with transcription factors and influence gene expression (4,11,12).ERK5 can be activated in response to a range of mitogenic stimuli [e.g., growth factors, G protein-coupled receptor (GPCR) agonists, cytokines] and cellular stresses (e.g., hypoxia, shear stress) (13). Like most kinases including MAPK members, ERK5 function is assumed to be driven by its kinase activity. ERK5 deletion is embryonic lethal in mice and a variety of tissue-or development-stage restricted KOs have shown clear phenotypes, suggesting that the catalytic function and/or an aspect of the nonkinase domain(s) have key roles in development and mature organ function (14-18). The availability of the first ERK5 inhibitor ...

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“…ERK5 has been recently studied as a target for mediating inflammation (23,24,26). We determined the activity of the ERK5 compounds in cellular assays of inflammatory response.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Lin¹,

Amantea²,

Nomanbhoy³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

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“…Finally, and expanding the relevance of ERK5 as a therapeutic target in cancer, ERK5 was recently reported to be a crucial mediator of inflammation and inflammation-driven cancer [103]. Inflammation is a major risk factor for the development of several types of cancer, being recognised as an enabling cancer feature [104].…”

Section: Other Cancer Typesmentioning

confidence: 99%

“…Inflammation is a major risk factor for the development of several types of cancer, being recognised as an enabling cancer feature [104]. It is believed that the inflammatory microenvironment supports the survival, sustained proliferation of cells, and angiogenesis, facilitating either tumour initiation and/or the malignant transformation of cancer cells [103]. Although others have suggested the anti-inflammatory role of MAPKs, two recent studies demonstrated that ERK5 was able to control the expression of several specific inflammatory mediators in response to a range of toll-like receptor (TLR) agonist and proinflammatory cytokines, which are essential for the establishment of the inflammatory microenvironment and, for instance, needed to support skin carcinogenesis [103].…”

Section: Other Cancer Typesmentioning

confidence: 99%

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

Simões

Rodrigues

Borralho

2016

Drug Discovery Today

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“…Accordingly, more attention may have to be paid in the putative role of ERK5 in reciprocal interactions between cells in the tumor to devise blood supply and a supportive immune environment. 2,7 …”

mentioning

confidence: 99%