scholarly journals Integrating Protein Localization with Automated Signaling Pathway Reconstruction

2019 ◽  
Author(s):  
Ibrahim Youssef ◽  
Jeffrey Law ◽  
Anna Ritz
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
Protein Interactions ◽  
Cellular Localization ◽  
Protein Localization ◽  
Dynamic Program ◽  
Reconstruction Algorithms ◽  
Ppi Networks ◽  
Cellular Compartments ◽  
Localization Information

AbstractUnderstanding cellular responses via signal transduction is a core focus in systems biology. Tools to automatically reconstruct signaling pathways from protein-protein interactions (PPIs) can help biologists generate testable hypotheses about signaling. However, automatic reconstruction of signaling pathways suffers from many interactions with the same confidence score leading to many equally good candidates. Further, some reconstructions are biologically misleading due to ignoring protein localization information. We proposeLocPL, a method to improve the automatic reconstruction of signaling pathways from PPIs by incorporating information about protein localization in the reconstructions. The method relies on a dynamic program to ensure that the proteins in a reconstruction are localized in cellular compartments that are consistent with signal transduction from the membrane to the nucleus.LocPLand existing reconstruction algorithms are applied to two PPI networks and assessed using both global and local definitions of accuracy.LocPLproduces more accurate and biologically meaningful reconstructions on a versatile set of signaling pathways.LocPLis a powerful tool to automatically reconstruct signaling pathways from PPIs that leverages cellular localization information about proteins. The underlying dynamic program and signaling model are flexible enough to study cellular signaling under different settings of signaling flow across the cellular compartments.

scholarly journals Integrating protein localization with automated signaling pathway reconstruction

2019 ◽  
Vol 20 (S16) ◽  
Author(s):  
Ibrahim Youssef ◽  
Jeffrey Law ◽  
Anna Ritz
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
Protein Interactions ◽  
Cellular Localization ◽  
Protein Localization ◽  
Dynamic Program ◽  
Reconstruction Algorithms ◽  
Ppi Networks ◽  
Cellular Compartments ◽  
Localization Information

Abstract Background Understanding cellular responses via signal transduction is a core focus in systems biology. Tools to automatically reconstruct signaling pathways from protein-protein interactions (PPIs) can help biologists generate testable hypotheses about signaling. However, automatic reconstruction of signaling pathways suffers from many interactions with the same confidence score leading to many equally good candidates. Further, some reconstructions are biologically misleading due to ignoring protein localization information. Results We propose LocPL, a method to improve the automatic reconstruction of signaling pathways from PPIs by incorporating information about protein localization in the reconstructions. The method relies on a dynamic program to ensure that the proteins in a reconstruction are localized in cellular compartments that are consistent with signal transduction from the membrane to the nucleus. LocPL and existing reconstruction algorithms are applied to two PPI networks and assessed using both global and local definitions of accuracy. LocPL produces more accurate and biologically meaningful reconstructions on a versatile set of signaling pathways. Conclusion LocPL is a powerful tool to automatically reconstruct signaling pathways from PPIs that leverages cellular localization information about proteins. The underlying dynamic program and signaling model are flexible enough to study cellular signaling under different settings of signaling flow across the cellular compartments.

scholarly journals Augmenting Signaling Pathway Reconstructions

2020 ◽  
Author(s):  
Tobias Rubel ◽  
Anna Ritz
Keyword(s):  
Signaling Pathways ◽  
Signaling Pathway ◽  
Protein Interactions ◽  
Cellular Response ◽  
Ground Truth ◽  
Protein Interaction Data ◽  
Reconstruction Method ◽  
Reconstruction Algorithms ◽  
Molecular Systems ◽  
Pathway Reconstruction

AbstractSignaling pathways drive cellular response, and understanding such pathways is fundamental to molecular systems biology. A mounting volume of experimental protein interaction data has motivated the development of algorithms to computationally reconstruct signaling pathways. However, existing methods suffer from low recall in recovering protein interactions in ground truth pathways, limiting our confidence in any new predictions for experimental validation. We present the Pathway Reconstruction AUGmenter (PRAUG), a higher-order function for producing high-quality pathway reconstruction algorithms. PRAUG modifies any existing pathway reconstruction method, resulting in augmented algorithms that outperform their un-augmented counterparts for six different algorithms across twenty-nine diverse signaling pathways. The algorithms produced by PRAUG collectively reveal potential new proteins and interactions involved in the Wnt and Notch signaling pathways. PRAUG offers a valuable framework for signaling pathway prediction and discovery.

scholarly journals Synthetic protein interactions reveal a functional map of the cell

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lisa K Berry ◽  
Guðjón Ólafsson ◽  
Elena Ledesma-Fernández ◽  
Peter H Thorpe
Keyword(s):  
Protein Interactions ◽  
Protein Localization ◽  
Eukaryotic Cells ◽  
Protein Protein Interactions ◽  
Yeast Saccharomyces Cerevisiae ◽  
Synthetic Protein ◽  
Protein Functions ◽  
Functional Map ◽  
Cellular Compartments ◽  
New Protein

To understand the function of eukaryotic cells, it is critical to understand the role of protein-protein interactions and protein localization. Currently, we do not know the importance of global protein localization nor do we understand to what extent the cell is permissive for new protein associations – a key requirement for the evolution of new protein functions. To answer this question, we fused every protein in the yeast Saccharomyces cerevisiae with a partner from each of the major cellular compartments and quantitatively assessed the effects upon growth. This analysis reveals that cells have a remarkable and unanticipated tolerance for forced protein associations, even if these associations lead to a proportion of the protein moving compartments within the cell. Furthermore, the interactions that do perturb growth provide a functional map of spatial protein regulation, identifying key regulatory complexes for the normal homeostasis of eukaryotic cells.

AUTOMATIC MODELING OF SIGNALING PATHWAYS BY NETWORK FLOW MODEL

2009 ◽  
Vol 07 (02) ◽  
pp. 309-322 ◽  
Author(s):  
XING-MING ZHAO ◽  
RUI-SHENG WANG ◽  
LUONAN CHEN ◽  
KAZUYUKI AIHARA
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
Protein Interaction ◽  
Network Flow ◽  
Computational Models ◽  
Flow Model ◽  
Mapk Signaling ◽  
Mixed Integer ◽  
Network Flow Model ◽  
Ppi Networks

Signal transduction is an important process that controls cell proliferation, metabolism, differentiation, and so on. Effective computational models which unravel such a process by taking advantage of high-throughput genomic and proteomic data are highly demanded to understand the essential mechanisms underlying signal transduction. Since protein–protein interaction (PPI) plays an important role in signal transduction, in this paper, we present a novel method for modeling signaling pathways from PPI networks automatically. Given an undirected weighted protein interaction network, finding signaling pathways is treated as searching for optimal subnetworks according to some cost function. To cope with this optimization problem, a network flow model is proposed in this work to extract signaling pathways from protein interaction networks. In particular, the network flow model is formalized and solved as a mixed integer linear programming (MILP) model, which is simple in algorithm and efficient in computation. The numerical results on two known yeast MAPK signaling pathways demonstrate the efficiency and effectiveness of the proposed method.

scholarly journals Peptide Signals Encode Protein Localization

2007 ◽  
Vol 189 (21) ◽  
pp. 7581-7585 ◽  
Author(s):  
Jay H. Russell ◽  
Kenneth C. Keiler
Keyword(s):  
Protein Interactions ◽  
Fluorescent Protein ◽  
Protein Localization ◽  
Protein Protein Interactions ◽  
Helical Structures ◽  
Bacterial Proteins ◽  
Complex Protein ◽  
Peptide Signals ◽  
Green Fluorescent ◽  
Localization Information

ABSTRACT Many bacterial proteins are localized to precise intracellular locations, but in most cases the mechanism for encoding localization information is not known. Screening libraries of peptides fused to green fluorescent protein identified sequences that directed the protein to helical structures or to midcell. These peptides indicate that protein localization can be encoded in 20-amino-acid peptides instead of complex protein-protein interactions and raise the possibility that the location of a protein within the cell could be predicted from bioinformatic data.

scholarly journals Short loop functional commonality identified in leukaemia proteome highlights crucial protein sub-networks

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Sun Sook Chung ◽  
Joseph C F Ng ◽  
Anna Laddach ◽  
N Shaun B Thomas ◽  
Franca Fraternali
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Interaction Network ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Ppi Networks ◽  
Short Loop ◽  
New Strategy ◽  
Loop Network ◽  
Protein Protein Interaction Network

Abstract Direct drug targeting of mutated proteins in cancer is not always possible and efficacy can be nullified by compensating protein–protein interactions (PPIs). Here, we establish an in silico pipeline to identify specific PPI sub-networks containing mutated proteins as potential targets, which we apply to mutation data of four different leukaemias. Our method is based on extracting cyclic interactions of a small number of proteins topologically and functionally linked in the Protein–Protein Interaction Network (PPIN), which we call short loop network motifs (SLM). We uncover a new property of PPINs named ‘short loop commonality’ to measure indirect PPIs occurring via common SLM interactions. This detects ‘modules’ of PPI networks enriched with annotated biological functions of proteins containing mutation hotspots, exemplified by FLT3 and other receptor tyrosine kinase proteins. We further identify functional dependency or mutual exclusivity of short loop commonality pairs in large-scale cellular CRISPR–Cas9 knockout screening data. Our pipeline provides a new strategy for identifying new therapeutic targets for drug discovery.

scholarly journals The Multifaceted Roles of USP15 in Signal Transduction

2021 ◽  
Vol 22 (9) ◽  
pp. 4728
Author(s):  
Tanuza Das ◽  
Eun Joo Song ◽  
Eunice EunKyeong Kim
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
Cellular Networks ◽  
Clinical Applications ◽  
Regulatory Mechanisms ◽  
Signaling Networks ◽  
Post Translational Modification ◽  
Comprehensive Overview ◽  
E3 Ligases ◽  
Disease Markers

Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly E3 ligases and deubiquitinases, have attracted attention for drug discovery. Here, we review recent findings on USP15, one of the deubiquitinases, which regulates diverse signaling pathways by deubiquitinating vital target proteins. Even though several basic previous studies have uncovered the versatile roles of USP15 in different signaling networks, those have not yet been systematically and specifically reviewed, which can provide important information about possible disease markers and clinical applications. This review will provide a comprehensive overview of our current understanding of the regulatory mechanisms of USP15 on different signaling pathways for which dynamic reverse ubiquitination is a key regulator.

scholarly journals cROStalk for Life: Uncovering ROS Signaling in Plants and Animal Systems, from Gametogenesis to Early Embryonic Development

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 525
Author(s):  
Valentina Lodde ◽  
Piero Morandini ◽  
Alex Costa ◽  
Irene Murgia ◽  
Ignacio Ezquer
Keyword(s):  
Signal Transduction ◽  
Signaling Pathways ◽  
Analytical Techniques ◽  
Antioxidant Systems ◽  
Developmental Studies ◽  
Science Field ◽  
Ros Signaling ◽  
Reproductive Processes

This review explores the role of reactive oxygen species (ROS)/Ca2+ in communication within reproductive structures in plants and animals. Many concepts have been described during the last years regarding how biosynthesis, generation products, antioxidant systems, and signal transduction involve ROS signaling, as well as its possible link with developmental processes and response to biotic and abiotic stresses. In this review, we first addressed classic key concepts in ROS and Ca2+ signaling in plants, both at the subcellular, cellular, and organ level. In the plant science field, during the last decades, new techniques have facilitated the in vivo monitoring of ROS signaling cascades. We will describe these powerful techniques in plants and compare them to those existing in animals. Development of new analytical techniques will facilitate the understanding of ROS signaling and their signal transduction pathways in plants and mammals. Many among those signaling pathways already have been studied in animals; therefore, a specific effort should be made to integrate this knowledge into plant biology. We here discuss examples of how changes in the ROS and Ca2+ signaling pathways can affect differentiation processes in plants, focusing specifically on reproductive processes where the ROS and Ca2+ signaling pathways influence the gametophyte functioning, sexual reproduction, and embryo formation in plants and animals. The study field regarding the role of ROS and Ca2+ in signal transduction is evolving continuously, which is why we reviewed the recent literature and propose here the potential targets affecting ROS in reproductive processes. We discuss the opportunities to integrate comparative developmental studies and experimental approaches into studies on the role of ROS/ Ca2+ in both plant and animal developmental biology studies, to further elucidate these crucial signaling pathways.

scholarly journals Targeted disruption of PKC from AKAP Signaling Complexes

2021 ◽  
Author(s):  
Ameya J. Limaye ◽  
George N. Bendzunas ◽  
Eileen Kennedy
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Signaling Pathways ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Targeted Disruption ◽  
Physiological Processes ◽  
Kinase C ◽  
P Protein

Protein Kinase C (PKC) is a member of the AGC subfamily of kinases and regulates a wide array of signaling pathways and physiological processes. Protein-protein interactions involving PKC and its...

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