Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ERK5 kinase activity is dispensable for cellular immune response and proliferation

ABSTRACT: 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 anti-inflammatory and anti-tumorigenic. 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 anti-inflammatory or anti-proliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains (BRDs), 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 non-catalytic 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE86577 | GEO | 2016/09/09

SECONDARY ACCESSION(S): PRJNA342296

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation

Project description:Over the past few decades, interest in the role that extracellular signal-regulated kinase 5 (ERK5) plays in various diseases, particularly cancer and inflammation, has grown. Phenotypes observed from genetic knockdown or deletion of ERK5 suggested that targeting ERK5 could have therapeutic potential in various disease settings, motivating the development of potent and selective ATP-competitive ERK5 inhibitors. However, these inhibitors were unable to recapitulate the effects of genetic loss of ERK5, suggesting that ERK5 may have key kinase-independent roles. To investigate potential non-catalytic functions associated with ERK5, we report here the development of INY-06-061, a potent and selective heterobifunctional degrader of ERK5. In contrast to results reported through genetic knockdown of ERK5, INY-06-061-induced ERK5 degradation did not induce anti-proliferative effects in multiple cancer cell lines or suppress inflammatory responses in primary endothelial cells. Thus, we have developed and characterized a chemical tool useful for validating phenotypes reported to be associated with genetic ERK5 ablation and for guiding future ERK5-directed drug discovery efforts.

2022-10-13 | PXD036104 | Pride

Acute pharmacological degradation of ERK5 does not inhibit cellular immune response or proliferation

2022-10-13 | PXD036105 | Pride

ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer [p826_PND_A549]

Project description:Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5) as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevents resistance to FAK inhibitors, significantly enhancing the efficacy of antitumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.

2024-09-16 | GSE255643 | GEO

ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer [p697_ERK5]

2024-09-16 | GSE255628 | GEO

ERK5 S496 phosphorylation, but not ERK5 kinase activation, promotes senescence-associated cell growth (SACG) and inflammation of myeloid cells and atherosclerosis via upregulating SUMOylation at a novel site (K518) on NRF2 and aryl hydrocarbon receptor

Project description:ERK5 is a dual kinase-transcription factor, which contains an N-terminal kinase domain and transactivation domains in the C-terminal half. Many ERK5 kinase inhibitors have been developed and tested to treat cancer and inflammatory diseases. However, recent data have raised questions regarding the functional role of ERK5 kinase inhibitors. We aimed to investigate how ERK5 reprograms myeloid cells (MC) to the senescence-associated secretory phenotype (SASP), consequently leading to atherosclerosis. We showed that atherosclerosis was inhibited in ERK5 S496A (dephosphorylation mimic) knock-in (KI) mice. Furthermore, ERK5 S496 phosphorylation was required for not only SASP but also senescence-associated cell growth (SACG) observed in the plaque via upregulation of aryl hydrocarbon receptor (AHR). We also discovered a key effect of ERK5 S496 phosphorylation on SUMOylation at a novel site of NRF2 (i.e., K518), which inhibited NRF2 transcriptional activity without affecting ERK5 kinase activity and antagonized oxidized LDL (oxLDL)-induced SASP. Specific ERK5 kinase inhibitors (AX15836 and XMD8-92) both inhibited oxLDL-induced ERK5 S496 phosphorylation, suggesting that ERK5 S496 phosphorylation was involved at least in part of the effects of these inhibitors. We have discovered a novel mechanism, in which ERK5 S496 phosphorylation directly inhibits NRF2 activity by upregulating NRF2 K518 SUMOylation, and induces SACG and atherosclerosis.

2023-06-09 | GSE210949 | GEO

Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling]

Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy. We included 15 samples from multiple myeloma cell lines.

2011-09-30 | E-GEOD-31421 | biostudies-arrayexpress

Central Inhibition of HDAC6 Re-Sensitizes Leptin Signaling During Obesity to Induce Profound Weight Loss

Project description:Leptin resistance during excess weigh gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of Leptin receptor b (LepR) signaling during obesity is still elusive. Here we report that histone deactylase 6 (HDAC6) interacts with LepR, reducing the latter’s activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of obese mice with blood brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to a potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in AgRP-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors result in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally-, but not peripherally-acting HDAC6 inhibitors as potent leptin-sensitizers and anti-obesity agents.

2024-01-09 | GSE252779 | GEO

Whole transcriptome analysis of endometroid cell lines after ERK5 inhibition

Project description:The transcriptomic network modulated after the inhibition of the nuclear tyrosin kinase ERK5 was analyzed Ishikawa endometroid cell line, in order to characterize and reveal any relevant role of this kinase at the transcriptional level.

2023-08-03 | GSE239920 | GEO

Whole transcriptome analysis of neuroblastoma cell lines after ERK5 silencing

Project description:The transcriptomic network modulated after the depletion of the tyrosin kinase ERK5 through shRNA-mediated silencing was analyzed in SK-N-BE(2) and CHLA-90 neuroblastoma cell lines, in order to characterize and reveal any relevant role of this kinase at the transcriptional level.

2022-10-29 | GSE216790 | GEO

Mitochondrial signatures shape phenotype switching and apoptosis in response to PLK1 and RSK inhibitiors in melanoma

Project description:PLK1 inhibitors are emerging anti-cancer agents being tested in monotherapy and combination therapies for various cancers. Although PLK1 inhibition in experimental models shows potent antitumor effects, translation to the clinic has been hampered by low antitumor activity and tumor relapse. Here, we report the identification of mitochondrial protein signatures that determine sensitivity to approaches targeting PLK1 in human melanoma cell lines. In response to PLK1 inhibition or gene silencing, resistant cells adopt a pro-inflammatory and dedifferentiated phenotype, while sensitive cells engage apoptosis. Mitochondrial DNA depletion and silencing of the ABCD1 transporter sensitize cells to PLK1 inhibition and attenuate the associated pro-inflammatory response. We also found that non-selective inhibitors of the p90 ribosomal S6 kinase (RSK) exert their anti-proliferative and pro-inflammatory effects via PLK1 inhibition. This work reveals overlooked impacts of PLK1 on phenotype switching and suggests that mitochondrial precision medicine can help improve response to targeted therapies.

2024-06-14 | GSE264686 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data