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IQGAP1 Scaffold-Kinase Interaction Blockade Selectively Targets Ras-MAP Kinase Driven Tumors

ABSTRACT: MAPK scaffolds, such as IQGAP1, assemble pathway kinases together to effect signal transmission and disrupting scaffold function therefore offers a potentially orthogonal approach to MAPK cascade inhibition. Consistent with this possibility, we observed an IQGAP1 requirement in Ras-driven tumorigenesis in mouse and human tissue. Delivery of the IQGAP1 WW peptide sequence that mediates Erk1/4 binding, moreover, disrupted IQGAP1-Erk1/2 interactions, abolished Ras/Raf-driven tumorigenesis, bypassed acquired resistance to the B-Raf inhibitor vemurafinib (PLX- 4032), and acts as a systemically deliverable therapeutic to significantly increase lifespan of tumor bearing mice. Scaffold-kinase interaction blockade (SKIB) acts by a mechanism distinct from direct kinase inhibition and represents a strategy to target over-active oncogenic kinase cascades in cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE44967 | GEO | 2013/04/01

SECONDARY ACCESSION(S): PRJNA192660

REPOSITORIES: GEO

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IQGAP1 Scaffold-Kinase Interaction Blockade Selectively Targets Ras-MAP Kinase Driven Tumors

Project description:MAPK scaffolds, such as IQGAP1, assemble pathway kinases together to effect signal transmission and disrupting scaffold function therefore offers a potentially orthogonal approach to MAPK cascade inhibition. Consistent with this possibility, we observed an IQGAP1 requirement in Ras-driven tumorigenesis in mouse and human tissue. Delivery of the IQGAP1 WW peptide sequence that mediates Erk1/4 binding, moreover, disrupted IQGAP1-Erk1/2 interactions, abolished Ras/Raf-driven tumorigenesis, bypassed acquired resistance to the B-Raf inhibitor vemurafinib (PLX- 4032), and acts as a systemically deliverable therapeutic to significantly increase lifespan of tumor bearing mice. Scaffold-kinase interaction blockade (SKIB) acts by a mechanism distinct from direct kinase inhibition and represents a strategy to target over-active oncogenic kinase cascades in cancer. Gene expression profiling: Fragmented cRNA was hybridized to the Mouse Gene 1.0 ST Array (Affymetrix). Iqgap1 wild-type and Iqgap1 knockout mouse treated with topical 4OHT for 0 days and 6 days days are compared.

2013-04-01 | E-GEOD-44967 | biostudies-arrayexpress

Mus musculus

Project description:IQGAP1 Scaffold-Kinase Interaction Blockade Selectively Targets Ras-MAP Kinase Driven Tumors

| PRJNA192660 | ENA

Erk1/2 mediated negative feedback regulation is essential for postnatal intestinal development and homeostasis

Project description:Objective: Homeostasis of intestinal stem cells (ISCs) is maintained by external niche signals and complicated intrinsic signaling networks. Mitogen-activated protein kinase (MAPK) cascades play pivotal roles in stem cell self-renewal and differentiation, but the functions and underlying molecular mechanisms are not fully understood. Design: We performed studies with mice deletion of Erk1/2 genes in intestinal epithelial cells at embryonic stages or a control mice. Intestinal tissues were collected and analyzed by histology, gene expression profiling, immunohistochemistry, immunfluorescence, western blotting and organoid culture. Organoids were treated with specific inhibitors for Ras or Akt activity. Mice were treated by intraperitoneal injection of rapamycin to inhibit mTOR signaling. Results: We found that deletion of Erk1/2 genes resulted in an unexpected increase in cell proliferation and migration, expansion of ISCs and formation of polyp-like structures, leading to postnatal death. Deficiency of epithelial Erk1/2 strongly impaired secretory cell differentiation and enterocyte maturation with aberrant Wnt signaling activation. Erk1/2 depletion resulted in loss of feedback regulation leading to Ras/Raf cascade activation. Ras then transactivated Akt activity to stimulate mTOR and phosphorylate β-catenin on Ser552. Suppression of Ras or Akt activity through specific inhibitors significantly repressed Akt downstream signaling and restored cell proliferation and differentiation phenotypes ex vivo. Moreover, inhibition of mTOR signaling by rapamycin partially rescued Erk1/2 depletion-induced intestinal defects and significantly prolonged mutant mouse life span. Conclusions Our study demonstrates an unexplored critical role of ERK/MAPK pathway negative feedback regulation of Akt/mTOR in intestine development and homeostasis, suggesting a complicated regulatory network in ISC function.

2020-08-10 | GSE134249 | GEO

eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations

Project description:The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a novel function of eIF4F in the negative regulation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for maintaining optimal ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.

2024-10-04 | GSE273721 | GEO

BRAF siRNA NHGRI_Liang_BRAF

Project description:BRAF, one of three RAF serine/threonine kinases (ARAF, BRAF and CRAF), plays a major role in the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling pathway, which mediates cellular responses to growth signals. Recently a high frequency (~60%-70%) of activating BRAF mutations (predominantly V600E) has been reported in malignant melanoma. In order to identify the downstream effects of BRAF signaling on melanoma cell growth and gene expression, cDNA microarray analysis was carried out following BRAF siRNA or MEK1/2 inhibitor (U0126) treatment. Keywords: time series, siRNA time series, siRNA, drug treatment

2013-07-07 | E-GEOD-5481 | biostudies-arrayexpress

Pan-Raf co-operates with PI3K-dependent signaling and critically contributes to myeloma cell survival independently of mutated RAS

Project description:The most common oncogenic mutations in multiple myeloma (MM) affect N- and K-RAS leading to constitutive activation of RAS-dependent signaling. Signal transduction via RAS, Raf and MAPK has been well described as a canonical pathway. In accordance with this assumption, we showed that the activity of the MEK/ERK module is strictly dependent on pan-Raf activity. However, inhibition of MEK/ERK has no or only minor effects on MM cell survival, whereas oncogenic Ras and pan-Raf critically contribute to survival of multiple myeloma cells. Therefore, we aimed to learn more about Raf-dependent but MEK-independent signaling effectors. We analyzed gene expression profiles in INA-6 cells after either pan-Raf inhibition with SB-590885 or MEK inhibition with PD-325901.

2016-11-21 | GSE75078 | GEO

BRAF siRNA NHGRI_Liang_BRAF

2013-07-07 | GSE5481 | GEO

Expression data from ERK1/2 null endothelial cells

Project description:Angiogenesis is a complex process orchestrated by both growth factors and cell adhesion to the extracellular matrix and is initiated by focal degradation of the vascular basement membrane with subsequent migration and proliferation of endothelial cells (EC). The Ras/Raf/MEK/ERK pathway is critical for EC function during angiogensis. Although in vitro studies implicate ERK1 and ERK2 in EC survival, their precise role in EC function in vivo remains poorly defined. Cre/loxP technology was used to inactivate Erk1 and Erk2 in EC during murine development, resulting in embryonic lethality due to a drastic reduction in angiogenesis. The angiogenic defect was linked to diminished EC proliferation and migration, but not to increased cell apoptosis. Expression of key cell cycle regulators was diminished in the double knockout cells. In addition, both Paxillin and Focal Adhesion Kinase were expressed at lower levels and failed to correctly localize to the cell membrane in EC lacking Erk1 and Erk2, leading to defects in the organization of the cytoskeleton and in cell motility. The results demonstrate that ERK1 and ERK2 coordinate cell proliferation and migration during angiogenesis. Lentivirus infected cells to generate ERK1/2 WT and ERK1/2 DKO endothelial cells were cultured, RNA was extracted and Affymetrix gene expression arrays were performed.

2010-07-30 | E-GEOD-16967 | biostudies-arrayexpress

LFQ of mouse brain in ischemic stroke

Project description:Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are part of the Raf/MEK/ERK1/2 cascade and are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. Therefore, this study aimed to investigate the impact of ERK1/2 after cerebral ischemia using transgenic mice with ubiquitous overexpression of ERK2 or of the Raf kinase inhibitor protein (RKIP), an inhibitor of the ERK1/2 signaling cascade.

2022-02-17 | PXD030067 | Pride

RNA-seq data of BRAF wild-type and BRAF mutant tumor cells treated with the ERK inhibitor GDC-0994

Project description:BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. Our date showed that the expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells.

2024-04-15 | GSE264049 | GEO

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