Gene expression profiles of Ras mutants.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE14934 | GEO | 2009/02/21
SECONDARY ACCESSION(S): PRJNA111929
REPOSITORIES: GEO
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Project description:Gene expression profiles were collected from HEK-HT cells expressing H-Ras with Ras-activating (G12V), Raf-activating (G12V,T35S), RalGEF-activating (G12V,E37G), or PI3K-activating (G12V,Y40C) mutations. Keywords: Comparison of Ras pathway components. THX=control; 12V=G12V mutation; 35S=G12V,T35S mutation; 37G=G12V,E37G mutation; 40C=G12V,Y40C mutation. 5 replicates of each. Total of 25 samples.
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2018-07-08 | MSV000082583 | MassIVE
Project description:Activating mutants of RAS are commonly found in many human cancers, but to date selective targeting of RAS in the clinic has been limited to KRAS(G12C) through covalent inhibitors. Here, we have developed a monobody, termed 12VC1, that recognizes the active state of both KRAS(G12V) and KRAS(G12C) up to 400-times more tightly than wild-type KRAS. Affinity purification were performed on PATU8902 and H358 cell lines that contain KRAS(G12V) and KRAS(G12C), respectively, but not from growth factor stimulated HEK293T cells containing only wild-type RAS. The mass spectrometric data was acquired in data dependent mode to show the clear enrichment of KRAS in the 2 cell lines that carry the mutated RAS. In addition, a targeted analysis was performed for the peptide carrying the G12V mutation as well as the wild type KRAS peptide to further verify enrichment of only the KRAS mutant.
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Project description:Identification of K-Ras and B-Raf mutations in colorectal cancer (CRC) is essential to predict patients' response to anti-EGFR therapy and formulate appropriate therapeutic strategies to improve prognosis and survival. Here, we combined parallel reaction monitoring (PRM) with high-field asymmetric waveform ion mobility (FAIMS) to enhance mass spectrometry sensitivity and improve the identification of low-abundance K-Ras and B-Raf mutations in biological samples without immunoaffinity enrichment. In targeted LC-MS/MS analyses, FAIMS reduced the occurrence of interfering ions and enhanced precursor ion purity, resulting in a three-fold improvement in the detection limit for K-Ras and B-Raf mutated peptides. In addition, ion mobility separation of isomeric peptides using FAIMS facilitated the unambiguous identification of K-Ras G12D and G13D peptides. The application of targeted LC-MS/MS analyses using FAIMS is demonstrated for the detection and quantitation of B-Raf V600E, K-Ras G12D, G13D, and G12V in CRC cell lines and primary specimens.
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Project description:Padala2017- ERK, PI3K/Akt and Wnt signalling
network (Ras mutated)
Crosstalk model of the ERK, Wnt and Akt
signalling pathways with Ras mutation.
This model is described in the article:
Cancerous perturbations
within the ERK, PI3K/Akt, and Wnt/?-catenin signaling network
constitutively activate inter-pathway positive feedback
loops.
Padala RR, Karnawat R, Viswanathan
SB, Thakkar AV, Das AB.
Mol Biosyst 2017 May; 13(5):
830-840
Abstract:
Perturbations in molecular signaling pathways are a result
of genetic or epigenetic alterations, which may lead to
malignant transformation of cells. Despite cellular robustness,
specific genetic or epigenetic changes of any gene can trigger
a cascade of failures, which result in the malfunctioning of
cell signaling pathways and lead to cancer phenotypes. The
extent of cellular robustness has a link with the architecture
of the network such as feedback and feedforward loops.
Perturbation in components within feedback loops causes a
transition from a regulated to a persistently activated state
and results in uncontrolled cell growth. This work represents
the mathematical and quantitative modeling of ERK, PI3K/Akt,
and Wnt/?-catenin signaling crosstalk to show the dynamics of
signaling responses during genetic and epigenetic changes in
cancer. ERK, PI3K/Akt, and Wnt/?-catenin signaling crosstalk
networks include both intra and inter-pathway feedback loops
which function in a controlled fashion in a healthy cell. Our
results show that cancerous perturbations of components such as
EGFR, Ras, B-Raf, PTEN, and components of the destruction
complex cause extreme fragility in the network and
constitutively activate inter-pathway positive feedback loops.
We observed that the aberrant signaling response due to the
failure of specific network components is transmitted
throughout the network via crosstalk, generating an additive
effect on cancer growth and proliferation.
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2019-08-21 | BIOMD0000000654 | BioModels
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2016-02-13 | E-GEOD-19295 | biostudies-arrayexpress
Project description:We discover drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network Achieving robust cancer-specific lethality is the ultimate clinical goal. Here we identify a compound with dual-inhibitory properties, named a131, that selectively kills cancer cells, while protecting normal cells. Through an unbiased CETSA screen, we identify the PIP4K lipid kinases as the target of a131. Ablation of the PIP4Ks generates a phenocopy of the pharmacological effects of PIP4K inhibition by a131. Notably, PIP4Ks inhibition by a131 causes reversible growth arrest in normal cells by transcriptionally up-regulating PIK3IP1, a suppressor of the PI3K/Akt/mTOR pathway. Strikingly, Ras activation overrides a131-induced PIK3IP1 up-regulation and activates the PI3K/Akt/mTOR pathway. Consequently, Ras-transformed cells override a131-induced growth arrest and enter mitosis where a131’s ability to de-cluster supernumerary centrosomes in cancer cells eliminates Ras-activated cells through mitotic catastrophe. Our discovery of drugs with a dual-inhibitory mechanism provides a unique pharmacological strategy against cancer and evidence of cross-activation between the Ras/Raf/MEK/ERK and PI3K/AKT/mTOR pathways via a Ras˧PIK3IP1˧PI3K signaling network.
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