Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy.

ABSTRACT: The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy.

SUBMITTER: Degirmenci U

PROVIDER: S-EPMC7017232 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy.

Degirmenci Ufuk U Wang Mei M Hu Jiancheng J

Cells 20200113 1

The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms invo ...[more]

PMID: 31941155

Similar Datasets

ErbB2 signaling epigenetically suppresses microRNA-205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer.

Project description:We previously reported that microRNA-205 (miR-205) is downregulated by overexpression of the receptor tyrosine kinase ErbB2 and that ectopic transfection of miR-205 precursor decreases ErbB2 tumorigenicity in soft agar. In this study, we further analyzed the regulatory mechanisms linking ErbB2 overexpression and miR-205 downregulation. In ErbB2-overexpressing breast epithelial cells, miR-205 expression was significantly increased by treatment with MEK inhibitor U0126 or PD98059, Raf-1 inhibitor ZM-336372, and ERK inhibitor SCH772984, but PI3K inhibitor LY294002 and p38 MAPK inhibitor SB203580 had no effect. We established breast epithelial cells overexpressing RafCAAX, a constitutively active form of Raf-1, and showed that overexpression of RafCAAX dramatically reduced miR-205 expression. In RafCAAX-overexpressing cells, miR-205 expression was also significantly increased by SCH772984. Moreover, miR-205 expression was significantly increased by treatment with DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine and expression of several DNMT family members was increased in both ErbB2- and RafCAAX-overexpressing cells. DNA methylation analysis by bisulfite sequencing revealed that the putative miR-205 promoters were predominantly hypermethylated in both ErbB2- and RafCAAX-overexpressing cells. Reporter activity of the putative miR-205 promoters was reduced in both ErbB2-overexpressing and RafCAAX-overexpressing cells. Together, these findings indicate that ErbB2 signaling epigenetically suppresses miR-205 transcription via the Ras/Raf/MEK/ERK pathway.

| S-EPMC5537069 | biostudies-literature

Polymorphisms in RAS/RAF/MEK/ERK Pathway Are Associated with Gastric Cancer.

Project description:The RAS/RAF/MEK/ERK pathway regulates certain cellular functions, including cell proliferation, differentiation, survival, and apoptosis. Dysregulation of this pathway leads to the occurrence and progression of cancers mainly by somatic mutations. This study aimed to assess if polymorphisms of the RAS/RAF/MEK/ERK pathway are associated with gastric cancer. A case-control study of 242 gastric cancer patients and 242 controls was performed to assess the association of 27 single nucleotide polymorphisms (SNPs) in the RAS/RAF/MEK/ERK pathway genes with gastric cancer. Analyses performed under the additive model (allele) showed four significantly associated SNPs: RAF1 rs3729931 (Odds ratio (OR) = 1.54, 95%, confidence interval (CI): 1.20⁻1.98, p-value = 7.95 × 10-4), HRAS rs45604736 (OR = 1.60, 95% CI: 1.16⁻2.22, p-value = 4.68 × 10-3), MAPK1 rs2283792 (OR = 1.45, 95% CI: 1.12⁻1.87, p-value = 4.91 × 10-3), and MAPK1 rs9610417 (OR = 0.60, 95% CI: 0.42⁻0.87, p-value = 6.64 × 10-3). Functional annotation suggested that those variants or their proxy variants may have a functional effect. In conclusion, this study suggests that RAF1 rs3729931, HRAS rs45604736, MAPK1 rs2283792, and MAPK1 rs9610417 are associated with gastric cancer.

| S-EPMC6356706 | biostudies-literature

CircRAPGEF5 acts as a modulator of RAS/RAF/MEK/ERK signaling during colorectal carcinogenesis.

Project description:Mutations in oncogenes such as KRAS, NRAS and BRAF promote the growth and survival of tumors, while excessive RAS/RAF/MEK/ERK activation inhibits tumor growth. In this study we examined the precise regulatory machinery that maintains a moderate RAS/RAF/MEK/ERK pathway activation during CRC. Here, using bioinformatic analysis, transcriptomic profiling, gene silencing and cellular assays we discovered that a circular RNA, circRAPGEF5, is significantly upregulated in KRAS mutant colorectal cancer (CRC) cells. CircRAPGEF5 suppressed mutant and constitutively activated KRAS and the expression of the death receptor TNFRSF10A. Silencing of circRAPGEF5-induced RAS/RAF/MEK/ERK signaling hyperactivation and apoptosis in CRC cells suggesting that an upregulation of circRAPEF5 may suppress the expression of TNFRSF10A and aid CRC progression by preventing apoptosis, while the direct interactions between circRAPGEF5 and elements of the RAS/RAF/MEK/ERK pathway was not identified, which nevertheless can be the basis for future research. Moreover, EIF4A3, was observed to share a similar expression pattern with circRAPEF5 and demonstrated to be a major controller of circRAPGEF5 via the promotion of circRAPGEF5 circularization and its silencing reduced circRAPGEF5 levels. Taken together, our findings reveal a mechanism of accurate RAS/RAF/MEK/ERK signaling regulation during CRC progression maintained by upregulation of circRAPGEF5 which may be a plausible target for future clinical applications that seek to induce CRC cell apoptosis via the RAS/RAF/MEK/ERK signaling pathway.

| S-EPMC11369509 | biostudies-literature

Direct Targeting of the Raf-MEK-ERK Signaling Cascade Inhibits Neuroblastoma Growth.

Project description:The Raf-MEK-ERK signaling network has been the subject of intense research due to its role in the development of human cancers, including pediatric neuroblastoma (NB). MEK and ERK are the central components of this signaling pathway and are attractive targets for cancer therapy. Approximately 3-5% of the primary NB samples and about 80% of relapsed samples contain mutations in the Raf-MEK-ERK pathway. In the present study, we analyzed the NB patient datasets and revealed that high RAF and MEK expression leads to poor overall survival and directly correlates with cancer progression and relapse. Further, we repurposed a specific small-molecule MEK inhibitor CI-1040 to inhibit the Raf-MEK-ERK pathway in NB. Our results show that CI-1040 potently inhibits NB cell proliferation and clonogenic growth in a dose-dependent manner. Inhibition of the Raf-MEK-ERK pathway by CI-1040 significantly enhances apoptosis, blocks cell cycle progression at the S phase, inhibits expression of the cell cycle-related genes, and significantly inhibits phosphorylation and activation of the ERK1/2 protein. Furthermore, CI-1040 significantly inhibits tumor growth in different NB 3D spheroidal tumor models in a dose-dependent manner and by directly inhibiting spheroidal tumor cells. Overall, our findings highlight that direct inhibition of the Raf-MEK-ERK pathway is a novel therapeutic approach for NB, and further developing repurposing strategies using CI-1040 is a clinically tractable strategy for effectively treating NB.

| S-EPMC9497977 | biostudies-literature

Inhibition of Ras/Raf/MEK/ERK Pathway Signaling by a Stress-Induced Phospho-Regulatory Circuit.

Project description:Ras pathway signaling plays a critical role in cell growth control and is often upregulated in human cancer. The Raf kinases selectively interact with GTP-bound Ras and are important effectors of Ras signaling, functioning as the initiating kinases in the ERK cascade. Here, we identify a route for the phospho-inhibition of Ras/Raf/MEK/ERK pathway signaling that is mediated by the stress-activated JNK cascade. We find that key Ras pathway components, the RasGEF Sos1 and the Rafs, are phosphorylated on multiple S/TP sites in response to JNK activation and that the hyperphosphorylation of these sites renders the Rafs and Sos1 unresponsive to upstream signals. This phospho-regulatory circuit is engaged by cancer therapeutics, such as rigosertib and paclitaxel/Taxol, that activate JNK through mitotic and oxidative stress as well as by physiological regulators of the JNK cascade and may function as a signaling checkpoint to suppress the Ras pathway during conditions of cellular stress.

| S-EPMC5135640 | biostudies-literature

Molecular signaling in multiple myeloma: association of RAS/RAF mutations and MEK/ERK pathway activation.

Project description:Multiple myeloma (MM) is a plasma cell malignancy that is still considered to be incurable in most cases. A dominant mutation cluster has been identified in RAS/RAF genes, emphasizing the potential significance of RAS/RAF/MEK/ERK signaling as a therapeutic target. As yet, however, the clinical relevance of this finding is unclear as clinical responses to MEK inhibition in RAS-mutant MM have been mixed. We therefore assessed RAS/RAF mutation status and MEK/ERK pathway activation by both targeted sequencing and phospho-ERK immunohistochemistry in 180 tissue biopsies from 103 patients with newly diagnosed MM (NDMM) and 77 patients with relapsed/refractory MM (rrMM). We found a significant enrichment of RAS/BRAF mutations in rrMM compared to NDMM (P=0.011), which was mainly due to an increase of NRAS mutations (P=0.010). As expected, BRAF mutations were significantly associated with activated downstream signaling. However, only KRAS and not NRAS mutations were associated with pathway activation compared to RAS/BRAFwt (P=0.030). More specifically, only KRASG12D and BRAFV600E were consistently associated with ERK activation (P<0.001 and P=0.006, respectively). Taken together, these results suggest the need for a more specific stratification strategy consisting of both confirmation of protein-level pathway activation as well as detailed RAS/RAF mutation status to allow for a more precise and more effective application of targeted therapies, for example, with BRAF/MEK inhibitors in MM.

| S-EPMC5523069 | biostudies-literature

KLF4 is regulated by RAS/RAF/MEK/ERK signaling through E2F1 and promotes melanoma cell growth.

Project description:Melanoma is the most lethal form of skin cancer and treatment of metastatic melanoma remains challenging. BRAF/MEK inhibitors show only temporary benefit due the occurrence of resistance and immunotherapy is effective only in a subset of patients. To improve patient survival, there is a need to better understand molecular mechanisms that drive melanoma growth and operate downstream of the mitogen activated protein kinase (MAPK) signaling. The Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor that plays a critical role in embryonic development, stemness and cancer, where it can act either as oncogene or tumor suppressor. KLF4 is highly expressed in post-mitotic epidermal cells, but its role in melanoma remains unknown. Here, we address the function of KLF4 in melanoma and its interaction with the MAPK signaling pathway. We find that KLF4 is highly expressed in a subset of human melanomas. Ectopic expression of KLF4 enhances melanoma cell growth by decreasing apoptosis. Conversely, knock-down of KLF4 reduces melanoma cell proliferation and induces cell death. In addition, depletion of KLF4 reduces melanoma xenograft growth in vivo. We find that the RAS/RAF/MEK/ERK signaling positively modulates KLF4 expression through the transcription factor E2F1, which directly binds to KLF4 promoter. Overall, our data demonstrate the pro-tumorigenic role of KLF4 in melanoma and uncover a novel ERK1/2-E2F1-KLF4 axis. These findings identify KLF4 as a possible new molecular target for designing novel therapeutic treatments to control melanoma growth.

| S-EPMC5474568 | biostudies-literature

Reusability and composability in process description maps: RAS-RAF-MEK-ERK signalling.

Project description:Detailed maps of the molecular basis of the disease are powerful tools for interpreting data and building predictive models. Modularity and composability are considered necessary network features for large-scale collaborative efforts to build comprehensive molecular descriptions of disease mechanisms. An effective way to create and manage large systems is to compose multiple subsystems. Composable network components could effectively harness the contributions of many individuals and enable teams to seamlessly assemble many individual components into comprehensive maps. We examine manually built versions of the RAS-RAF-MEK-ERK cascade from the Atlas of Cancer Signalling Network, PANTHER and Reactome databases and review them in terms of their reusability and composability for assembling new disease models. We identify design principles for managing complex systems that could make it easier for investigators to share and reuse network components. We demonstrate the main challenges including incompatible levels of detail and ambiguous representation of complexes and highlight the need to address these challenges.

| S-EPMC8425390 | biostudies-literature

Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway.

Project description:The Ras family of small GTPases constitutes a central node in the transmission of mitogenic stimuli to the cell cycle machinery. The ultimate receptor of these mitogenic signals is the retinoblastoma (Rb) family of pocket proteins, whose inactivation is a required step to license cell proliferation. However, little is known regarding the molecular events that connect Ras signaling with the cell cycle. Here, we provide genetic evidence to illustrate that the p53/p21 Cdk-interacting protein 1 (Cip1)/Rb axis is an essential component of the Ras signaling pathway. Indeed, knockdown of p53, p21Cip1, or Rb restores proliferative properties in cells arrested by ablation of the three Ras loci, H-, N- and K-Ras. Ras signaling selectively inactivates p53-mediated induction of p21Cip1 expression by inhibiting acetylation of specific lysine residues in the p53 DNA binding domain. Proliferation of cells lacking both Ras proteins and p53 can be prevented by reexpression of the human p53 ortholog, provided that it retains an active DNA binding domain and an intact lysine residue at position 164. These results unveil a previously unidentified role for p53 in preventing cell proliferation under unfavorable mitogenic conditions. Moreover, we provide evidence that cells lacking Ras and p53 proteins owe their proliferative properties to the unexpected retroactivation of the Raf/Mek/Erk cascade by a Ras-independent mechanism.

| S-EPMC4210339 | biostudies-literature

CREBBP knockdown enhances RAS/RAF/MEK/ERK signaling in Ras pathway mutated acute lymphoblastic leukemia but does not modulate chemotherapeutic response.

Project description:Relapsed acute lymphoblastic leukemia is the most common cause of cancer-related mortality in young people and new therapeutic strategies are needed to improve outcome. Recent studies have shown that heterozygous inactivating mutations in the histone acetyl transferase, CREBBP, are particularly frequent in relapsed childhood acute lymphoblastic leukemia and associated with a hyperdiploid karyotype and KRAS mutations. To study the functional impact of CREBBP haploinsufficiency in acute lymphoblastic leukemia, RNA interference was used to knock down expression of CREBBP in acute lymphoblastic leukemia cell lines and various primagraft acute lymphoblastic leukemia cells. We demonstrate that attenuation of CREBBP results in reduced acetylation of histone 3 lysine 18, but has no significant impact on cAMP-dependent target gene expression. Impaired induction of glucocorticoid receptor targets was only seen in 1 of 4 CREBBP knockdown models, and there was no significant difference in glucocorticoid-induced apoptosis, sensitivity to other acute lymphoblastic leukemia chemotherapeutics or histone deacetylase inhibitors. Importantly, we show that CREBBP directly acetylates KRAS and that CREBBP knockdown enhances signaling of the RAS/RAF/MEK/ERK pathway in Ras pathway mutated acute lymphoblastic leukemia cells, which are still sensitive to MEK inhibitors. Thus, CREBBP mutations might assist in enhancing oncogenic RAS signaling in acute lymphoblastic leukemia but do not alter response to MEK inhibitors.

| S-EPMC5395114 | biostudies-literature

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