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Phosphoproteomic analysis of MAPK signaling

ABSTRACT: Using label-free mass spectrometry, we measured phosphorylation changes in response to inhibition of MAPK.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Colon Cancer

SUBMITTER: Florian Gnad

LAB HEAD: Florian Gnad

PROVIDER: PXD003908 | Pride | 2016-07-22

REPOSITORIES: Pride

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			Action	DRS
	120710_11070_MS_SERVICE_o.RAW	Raw
	120710_11071_MS_SERVICE_o.RAW	Raw
	120710_11072_MS_SERVICE_o.RAW	Raw
	120710_11073_MS_SERVICE_o.RAW	Raw
	120810_11074_MS_SERVICE_o.RAW	Raw

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Publications

Phosphoproteome analysis of the MAPK pathway reveals previously undetected feedback mechanisms.

Gnad Florian F Doll Sophia S Song Kyung K Stokes Matthew P MP Moffat John J Liu Bonnie B Arnott David D Wallin Jeffrey J Friedman Lori S LS Hatzivassiliou Georgia G Belvin Marcia M

Proteomics 20160701 14

The RAS-RAF-MEK-ERK (MAPK) pathway is prevalently perturbed in cancer. Recent large-scale sequencing initiatives profiled thousands of tumors providing insight into alterations at the DNA and RNA levels. These efforts confirmed that key nodes of the MAPK pathway, in particular KRAS and BRAF, are among the most frequently altered proteins in cancer. The establishment of targeted therapies, however, has proven difficult. To decipher the underlying challenges, it is essential to decrypt the phospho ...[more]

PMID: 27273156

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Phosphoproteomic analysis of PI3K signaling

Project description:Using label-free mass spectrometry, we measured phosphorylation changes in response to activation or inhibition of PI3K.

2016-07-22 | PXD003899 | Pride

Quantitative Tyr Phosphoproteomic Analyses of Tumor Adaptive Response to MAPK Inhibition

Project description:Although targeted inhibition of the MAPK pathway has achieved remarkable patient responses in many cancers with MAPK hyperactivation, the development of resistance has remained a critical challenge. Besides genomic resistance mechanisms, adaptive tumor response also underlies the resistance to targeted MAPK inhibitors. It is being increasingly appreciated that such bypass mechanisms often lead to the activation of many pro-survival kinases, which complicates the rational design of combination therapies. Here we performed global tyrosine phosphoproteomic (pTyr) analyses and demonstrated that targeted inhibition of MAPK signaling in melanoma cells leads to a profound remodeling of the pTyr proteome. Intriguingly, many of these kinases contain a cholesterol binding motif, suggesting that altered cholesterol metabolism might drive, in a coordinated fashion, the activation of these kinases. Indeed, we found a dramatic accumulation of intracellular cholesterol in melanoma cells (with BRAFV600E mutations) and non-small cell lung cancer cells (with KRasG12C mutations) treated with MAPK and KrasG12C inhibitors, respectively. Importantly, depletion of cholesterol not only prevents the MAPK inhibition-induced feedback activation of pTyr singling but also enhances the cytotoxic effects of MAPK inhibitors, both in vitro and in vivo. Taken together, our findings provide the evidence suggesting that cholesterol functions as a master regulator of the tumor adaptive response to targeted MAPK inhibitors. These results also suggest that MAPK inhibitors could be combined with cholesterol-lowering agents to achieve a more complete and durable response in tumors with hyperactive MAPK signaling.

2021-05-11 | PXD021877 | Pride

MAPK

Project description:MAPK

| PRJNA1054526 | ENA

RNA-seq of Glioma Neural Stem (GNS) cell line G144 after MEK inhibition in wild type (WT) and CIC (Capicua) depleted cells.

Project description:We identified genome-wide binding patterns of CIC in several different cell types and find that CIC target genes are enriched for MAPK effector genes involved in cell cycle regulation and proliferation. CIC binding to its target genes is abolished by high MAPK activity, which leads to hyperacetylation and their transcriptional activation. Inhibition of MAPK signaling via MEK inhibition leads to recruitment of CIC to its target genes. ChIP-seq data of G144 cells after MEK inhibition and CIC knockout is available under accession E-MTAB-6682

2018-05-31 | E-MTAB-6681 | biostudies-arrayexpress

ChIP-seq of CIC (Capicua) and histone marks (H3K9ac, H3K27ac and H3K4me1) in glioma neural stem cells (GNS) G144, human foetal neural stem cells (hNSC) and mouse embryonic stem cells (mESC),

Project description:We identified genome-wide binding patterns of CIC in several different cell types and find that CIC target genes are enriched for MAPK effector genes involved in cell cycle regulation and proliferation. CIC binding to its target genes is abolished by high MAPK activity, which leads to hyperacetylation and their transcriptional activation. Inhibition of MAPK signaling via MEK inhibition leads to recruitment of CIC to its target genes. Expression data of G144 cells after MEK inhibition and CIC knockout is available under accession E-MTAB-6681

2018-05-31 | E-MTAB-6682 | biostudies-arrayexpress

Melanoma NRAS - Cooperative induction of apoptosis in nras mutant melanoma by inhibition of mek and rock

Project description:In the present work we propose a new therapy for NRAS mutant melanoma. Simultaneous inhibition of MEK and ROCK caused induction of BimEL , PARP, and Puma, and hence apoptosis. In vivo, MEK and ROCK inhibition suppressed growth of established tumors. Our findings warrant clinical investigation of the effectiveness of combinatorial targeting of MAPK/ERK and ROCK in NRAS mutant melanoma.

2015-03-11 | PXD000528 | Pride

Transcriptional Profiling Defines the Roles of ERK and p38 Kinases in Epidermal Keratinocytes

Project description:Epidermal keratinocytes respond to extracellular influences by activating cytoplasmic signal transduction pathways that change the transcriptional profiles of affected cells. To define responses to two such pathways, p38 and ERK, we used SB203580 and PD98059 as specific inhibitors, and identified the regulated genes after 1, 4, 24 and 48 hrs, using Affymetrix’ Hu133Av2 microarrays. Additionally, we compared genes specifically regulated by p38 and ERKs with those regulated by JNK and by all three pathways simultaneously. We find that the p38 pathway induces the expression of extracellular matrix and proliferation-associated genes, while suppressing microtubule-associated genes; the ERK pathway induces the expression of nuclear envelope and mRNA splicing proteins, while suppressing steroid synthesis and mitochondrial energy production enzymes. Both pathways promote epidermal differentiation and induce feedback inactivation of MAPK signaling. c-FOS, SRY and N-Myc appear to be the principal targets of the p38 pathway, Elk-1 SAP1 and HLH2 of ERK, while FREAC-4, ARNT and USF are common to both. The results for the first time comprehensively define the genes regulated by the p38 and ERK pathways in epidermal keratinocytes and suggest a list of targets potentially useful in therapeutic interventions. Human epidermal keratinocytes are grown in Keratinocyte Serum-Free Medium (Gibco) supplemented with 0.05 mg/ml bovine pituitary extract, 2.5 ng/ml epidermal growth factor, 0.09 mM CalCl2 and 1% penicillin/streptomycin (KGM). They are switched to Keratinocyte Serum Free-Media (Gibco) supplemented only with 1% penicillin/streptomycin (KBM) 24 h prior to commencing experiments. A set is left as controls, others treated with 5 uM JNK inhibitor SP600125, 15 uM p38 inhibitor SB203580, or 50 um ERK inhibitor PD98059. Timecourse of treated and parellel control samples over a 48 hr period was performed.

2013-09-05 | E-GEOD-50591 | biostudies-arrayexpress

Dyrk1a P60 phosphoproteomic data

Project description:Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice leads to ASD-related phenotypes, although key pathological mechanisms remain unclear. In addition, human DYRK1A mutations have not been characterized in mice. Here we report Dyrk1a-knockin mice carrying a human mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteome patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues brain volume, behavior, dendrite, synapse, and signaling/synapse phospho-proteome phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to phenotypic alterations in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects of preventing juvenile and adult-stage phenotypes.

2024-12-04 | PXD050100 | Pride

Phosphorylation ratio of pT vs pY ERK in MEK phosphorylation reaction determined by mass spectrometry

Project description:The purpose of this experiment is to determine the phosphorylation ratio of pT vs pY ERK present in ERK phosphorylation reaction by activated MEK E203K or MEK WildType. Aliquots were collected at 3 minutes 15 seconds, the time at which the mono-phosphorylated ERK is at its maximal. To determine the ratio between pT and pY ERK, synthetic AQUA peptides corresponding to the pY- and the pT-phosphorylated ERK were spiked into the sample. The two peptides have identical mass but they can be umabiguguously distinguished by their elution times and fragmentation spectra.

2020-01-14 | PXD016580 | Pride

Transcription profiling of Drosophila SL2 cells treated with E. coli with RNAi knock-down of Dsor1 or Gap1

Project description:Experiment was undertaken to compare the transcriptional response of SL2 cells to E. coli treatment with the response to modulated ERK/MAPK activity through RNAi of Dsor1 or Gap1.

2009-10-01 | E-MEXP-2145 | biostudies-arrayexpress

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