Mutational Forks: Inferring Deregulated Flow of Signal Transduction Based on Patient-Specific Mutations

Modeling signal transduction in cancer cells has implications for targeting new therapies and inferring the mechanisms that improve or threaten a patient's treatment response. For transcriptome-wide studies, it has been proposed that simple correlation between a ligand and receptor pair implies a relationship to the disease process. Statistically, a differential correlation (DC) analysis across groups stratified by prognosis can link the pair to clinical outcomes. While the prognostic effect and the apparent change in correlation are both biological consequences of activation of the signaling mechanism, a correlation-driven analysis does not clearly capture this assumption and makes inefficient use of continuous survival phenotypes. To augment the correlation hypothesis, we propose that a regression framework assuming a patient-specific, latent level of signaling activation exists and generates both prognosis and correlation. Data from these systems can be inferred via interaction terms in survival regression models allowing signal transduction models beyond one pair at a time and adjusting for other factors. We illustrate the use of this model on ovarian cancer data from the Cancer Genome Atlas (TCGA) and discuss how the finding may be used to develop markers to guide targeted molecular therapies.

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Individualised Proteogenomics Applied to Analysis of Amino Acid Variants in Malignant Melanoma

10.1101/2020.12.15.422879 ◽

2020 ◽

Author(s):

Marisa Schmitt ◽

Tobias Sinnberg ◽

Katrin Bratl ◽

Claus Garbe ◽

Boris Macek ◽

...

Keyword(s):

Signal Transduction ◽

Amino Acid ◽

Malignant Melanoma ◽

Personalised Medicine ◽

Phosphorylation Site ◽

Patient Specific ◽

Special Importance ◽

Signal Transduction Networks ◽

The Impact ◽

A375 Cells

Analysis of patient-specific nucleotide variants is a cornerstone of personalised medicine. Although only 2% of the genomic sequence is protein-coding, mutations occurring in these regions have the potential to influence protein structure and may have severe impact on disease aetiology. Of special importance are variants that affect modifiable amino acid residues, as protein modifications involved in signal transduction networks cannot be analysed by genomics. Proteogenomics enables analysis of proteomes in context of patient- or tissue-specific non-synonymous nucleotide variants. Here we developed an individualised proteogenomics workflow and applied it to study resistance to BRAF inhibitor vemurafenib in malignant melanoma cell line A375. This approach resulted in high identification and quantification of non-synonymous nucleotide variants, transcripts and (phospho)proteins. We integrated multi-omic datasets to reconstruct the perturbed signalling networks associated with BRAFi resistance, prioritise key actionable nodes and predict drug therapies with potential to disrupt BRAFi resistance mechanism in A375 cells. Notably, we showed that AURKA inhibition is effective and specific against BRAFi resistant A375 cells. Furthermore, we investigated nucleotide variants that interfere with protein modification status and potentially influence signal transduction networks. Mass spectrometry (MS) measurements confirmed variant-driven modification changes in approximately 50 proteins; among them was the transcription factor RUNX1 displaying a variant on a known phosphorylation site S(Ph)276L. We confirmed the loss of phosphorylation site by MS and demonstrated the impact of this variant on RUNX1 interactome. Our study paves the way for large-scale application of proteogenomics in melanoma.

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Identifying patient-specific flow of signal transduction perturbed by multiple single-nucleotide alterations

Quantitative Biology ◽

10.1007/s40484-020-0227-0 ◽

2020 ◽

Vol 8 (4) ◽

pp. 336-346

Author(s):

Olha Kholod ◽

Chi-Ren Shyu ◽

Jonathan Mitchem ◽

Jussuf Kaifi ◽

Dmitriy Shin

Keyword(s):

Signal Transduction ◽

Patient Specific ◽

Specific Flow ◽

Single Nucleotide

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Ultrastructural aspects of olfactory signal transduction and its development

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010016844x ◽

1994 ◽

Vol 52 ◽

pp. 142-143

Author(s):

Bert Ph. M. Menco

Keyword(s):

Signal Transduction ◽

Olfactory Receptor ◽

Receptor Cell ◽

Freeze Substitution ◽

Luminal Surface ◽

Tissue Sections ◽

Olfactory Receptor Cells ◽

Receptor Cells ◽

Olfactory Signal ◽

Odor Molecule

Vertebrate olfactory receptor cells are specialized neurons that have numerous long tapering cilia. The distal parts of these cilia line the interface between the external odorous environment and the luminal surface of the olfactory epithelium. The length and number of these cilia results in a large surface area that presumably increases the chance that an odor molecule will meet a receptor cell. Advanced methods of cryoprepration and immuno-gold labeling were particularly useful to preserve the delicate ultrastructural and immunocytochemical features of olfactory cilia required for localization of molecules involved in olfactory signal-transduction. We subjected olfactory tissues to freeze-substitution in acetone (unfixed tissues) or methanol (fixed tissues) followed by low temperature embedding in Lowicryl K11M for that purpose. Tissue sections were immunoreacted with several antibodies against proteins that are presumably important in olfactory signal-transduction.

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Signal-regulated oxidation of proteins via MICAL

Biochemical Society Transactions ◽

10.1042/bst20190866 ◽

2020 ◽

Vol 48 (2) ◽

pp. 613-620

Author(s):

Clara Ortegón Salas ◽

Katharina Schneider ◽

Christopher Horst Lillig ◽

Manuela Gellert

Keyword(s):

Signal Transduction ◽

Hydrogen Peroxide ◽

Cell Death ◽

Redox Regulation ◽

Signal Transduction Pathways ◽

Cellular Functions ◽

Intracellular Signals ◽

Amino Acid Side Chains ◽

Specific Receptors ◽

Sulfur Containing

Processing of and responding to various signals is an essential cellular function that influences survival, homeostasis, development, and cell death. Extra- or intracellular signals are perceived via specific receptors and transduced in a particular signalling pathway that results in a precise response. Reversible post-translational redox modifications of cysteinyl and methionyl residues have been characterised in countless signal transduction pathways. Due to the low reactivity of most sulfur-containing amino acid side chains with hydrogen peroxide, for instance, and also to ensure specificity, redox signalling requires catalysis, just like phosphorylation signalling requires kinases and phosphatases. While reducing enzymes of both cysteinyl- and methionyl-derivates have been characterised in great detail before, the discovery and characterisation of MICAL proteins evinced the first examples of specific oxidases in signal transduction. This article provides an overview of the functions of MICAL proteins in the redox regulation of cellular functions.

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