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Interleukin-7 Receptor signaling network:An Integrated Systems Perspective

Cellular & Molecular Immunology 2008年第2期5卷 79-89页

作者： Megan J. Palmer Vinay S. Mahajan Lily C. Trajman Darrell J. Irvine Douglas A.Lauffenburger Jianzhu Chen Department of Biological Engineering Koch Institute for Integrative Cancer Research and Department of Biology Massachusetts Institute of Technology Cambridge MA 02139 USA

Interleukin-7 （IL-7） is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes. Binding of IL-7 to its cognate receptor, the IL-7 receptor （IL-7R）, activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. There has been much interest in understanding how IL-7 receptor signaling is modulated at multiple interconnected network levels. This review examines how the strength of the signal through the IL-7 receptor is modulated in T and B cells, including the use of shared receptor components, signaling crosstalk, shared interaction domains, feedback loops, integrated gene regulation, multimerization and ligand competition. We discuss how these network control mechanisms could integrate to govern the properties of IL-7R signaling in lymphocytes in health and disease. Analysis of IL-7 receptor signaling at a network level in a systematic manner will allow for a comprehensive approach to understanding the impact of multiple signaling pathways on lymphocyte biology. Cellular ＆ Molecular Immunology.

关键词： IL-7 receptor cytokine signaling network systems biology modeling

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Nitric oxide:A potential key point of the signaling network leading to plant secondary metabolite biosynthesis

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Progress in Natural Science:Materials International 2007年第12期17卷 1397-1404页

作者： Xu Maojun(Department of Biotechnology, Zhejiang Gongshang University, Hangzhou 310035, China) Department of Biotechnology Zhejiang Gongshang University Hangzhou 310035 China

The endogenous signaling network of plants plays important roles in mediating the exogenous factor-induced biosynthesis of secondary metabolites. Nitric oxide (NO) has emerged as a key signaling molecule in plants recently. Numerous studies demonstrated that the main signaling molecules such as salicylic acid (SA), jasmonic acid (JA), reactive oxygen species (ROS), and NO were not only involved in regulating plant secondary metabolite biosynthesis but also interacted to form a complex signaling network by mutual inhibition and/or synergy. The recent progress in the signal network of plant secondary metabolite biosynthesis has been discussed in this paper. Furthermore, we propose a hypothetical model to show that NO might act as a potential molecular switch in the signaling network leading to plant secondary metabolite biosynthesis.

关键词： plant secondary metabolites biosynthesis signaling network nitric oxide salicylic acid jasmonic acid reactive oxygen species.

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McSNAC:A software to approximate first-order signaling networks from mass cytometry data

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Quantitative Biology 2023年第1期11卷 59-71页

作者： Darren Wethington Sayak Mukherjee Jayajit Das Steve and Cindy Rasmussen Institute for Genomic Medicine Abigail Wexner Research InstituteNationwide Children’s HospitalColumbusOhio 43205United States Biomedical Sciences Graduate Program College of MedicineThe Ohio State UniversityColumbusOhio 43210United States Department of Pediatrics College of MedicineThe Ohio State UniversityColumbusOhio 43210United States Pelotonia Institute for Immuno-Oncology College of MedicineThe Ohio State UniversityColumbusOhio 43210United States DepartmentofBiomedicalInformatics CollegeofMedicineTheOhioStateUniversityColumbusOhio43210United States Biophysics Graduate Program The Ohio State UniversityColumbusOhio 43210United States Battelle Memorial Institute ColumbusOhio 43201United States

Background:Mass cytometry(CyTOF)gives unprecedented opportunity to simultaneously measure up to 40 proteins in single cells,with a theoretical potential to reach 100 proteins.This high-dimensional single-cell information can be very useful in dissecting mechanisms of cellular activity.In particular,measuring abundances of signaling proteins like phospho-proteins can provide detailed information on the dynamics of single-cell signaling processes.However,computational analysis is required to reconstruct such networks with a mechanistic model.Methods:We propose our Mass cytometry signaling network Analysis Code(McSNAC),a new software capable of reconstructing signaling networks and estimating their kinetic parameters from CyTOF data.McSNAC approximates signaling networks as a network of first-order reactions between proteins.This assumption often breaks down as signaling reactions can involve binding and unbinding,enzymatic reactions,and other nonlinear constructions.Furthermore,McSNAC may be limited to approximating indirect interactions between protein species,as cytometry experiments are only able to assay a small fraction of protein species involved in signaling.Results:We carry out a series of in silico experiments here to show(1)McSNAC is capable of accurately estimating the ground-truth model in a scalable manner when given data originating from a first-order system;(2)McSNAC is capable of qualitatively predicting outcomes to perturbations of species abundances in simple second-order reaction models and in a complex in silico nonlinear signaling network in which some proteins are unmeasured.Conclusions:These findings demonstrate that McSNAC can be a valuable screening tool for generating models of signaling networks from time-stamped CyTOF data.

关键词： single-cell CyTOF data signaling network kinetics ODE McSNAC

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network-based identification of feedback modules that control RhoA activity and cell migration

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分子细胞生物学报:英文版 2015年第3期7卷 242-252页

作者： Tae-Hwan Kim Naser Monsefi Je-Hoon Song Alex von Kriegsheim Drieke Vandamme Olivier Pertz Boris NKholodenko Walter Kolch Kwang-Hyun Cho Department of Bio and Brain Engineering Korea Advanced Institute of Science and Technology(KAIST)Daejeon 305-701Republic of Korea Systems Biology Ireland University College DublinBelfieldDublin 4Ireland Department of Biomedicine University of BaselBaselSwitzerland School of Medicine and Medical Science University College DublinBelfieldDublin 4Ireland Conway Institute of Biomolecular&Biomedical Research University College DublinBelfieldDublin 4Ireland

Cancer cell migration enables metastatic spread causing most cancer deaths.Rho-family GTPases control cell migration,but being embedded in a highly interconnected feedback network,the control of their dynamical behavior during cell migration remains elusive.To address this question,wereconstructed the Rho-family GTPases signaling network involved in cell migration,and developed a Boolean network model to analyze the different states and emergent rewiring of the Rho-family GTPases signaling network at protrusions and during extracellular matrix-dependent cell migration.Extensive simulations and experimental validations revealed that the bursts of RhoA activity induced at protrusions by EGFare regulated by a negative-feedback module composed of Src,FAK,and CSK.Interestingly,perturbing this module interfered with cyclic Rho activation and extracellular matrix-dependent migration,suggesting that CSK inhibition can be a novel and effective intervention strategy for blocking extracellular matrix-dependent cancer cell migration,while Src inhibition might fail,depending on the genetic background of cells.Thus,this study provides new insights into the mechanisms that regulate the intricate activation states of Rho-family GTPases during extracellular matrix-dependent migration,revealing potential new targets for interfering with extracellular matrix-dependent cancer cell migration.

关键词： cell migration Rho-family GTPases signaling network Boolean network model cyclical RhoA bursts

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Comparative Analysis of Human Genes Frequently and Occasionally Regulated by m^6A Modification

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Genomics, Proteomics & Bioinformatics 2018年第2期16卷 127-135页

作者： Yuan Zhou Qinghua Cui Department of Biomedical Informatics School of Basic Medical Sciences Peking University

The m^6A modification has been implicated as an important epitranscriptomic marker, which plays extensive roles in the regulation of transcript stability, splicing, translation, and localization. Nevertheless, only some genes are repeatedly modified across various conditions and the principle of m^6A regulation remains elusive. In this study, we performed a systems-level analysis of human genes frequently regulated by m^6A modification （m^6Afreq genes） and those occasionally regulated by m^6A modification （m^6Aocca genes）. Compared to the m^6Aocca genes, the m^6Afreq genes exhibit gene importance-related features, such as lower dN/dS ratio, higher protein-protein interaction network degree, and reduced tissue expression specificity. signaling network analysis indicates that the m^6Afreq genes are associated with downstream components of signaling cascades, high-linked signaling adaptors, and specific network motifs like incoherent feed forward loops. Moreover, functional enrichment analysis indicates significant overlaps between the m^6Afreq genes and genes involved in various layers of gene expression, such as being the microRNA targets and the regulators of RNA processing. Therefore, our findings suggest the potential interplay between m^6A epitranscriptomic regulation and other gene expression regulatory machineries.

关键词： m^6A Epitranscriptome signaling network Gene expression regulation Gene importance

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System control-mediated drug delivery towards complex systems via nanodiamond carriers

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International Journal of Smart and Nano Materials 2010年第1期1卷 69-81页

作者： Dean Ho Chih-Ming Ho Department of Biomedical Engineering Department of Mechanical Engineering Northwestern UniversityEvanstonIL 60208USA Robert H.Lurie Comprehensive Cancer Center Northwestern UniversityChicagoIL 60611USA Department of Mechanical and Aerospace Engineering University of CaliforniaLos AngelesLACA 90095USA Center for Cell Control A NIH Nanomedicine Development CenterLos AngelesCA 90095USA

Cells represent the basic units of life and contain an intertwined network of signaling and regulatory circuitries that drive the processes of life.These processes include the mediation of mechano-sensation,onset of and protection against disease,inflammation,and others.In the network of bio-complex systems,each pathway interacts nonlinearly with others through different molecular intermediates.As a result,specific functionalities can not be simply linked to the cellular molecules in isolation.A complex system generally possesses very rich information content that can be characterized by the following features:(i)they contain a large number of building blocks;(ii)their interactions among building blocks and with their environment;(iii)they display organization without an external organizing principle being applied;and(iv)they exhibit adaptability and robustness.These properties account for the innate intelligence of biology and its ability to regulate its homeostatic behavior.However,this same complexity underlies,in cancer for example,challenges towards disease management,as the addressing of singular pathways with therapeutic compounds is not sufficient.Therefore,combinatorial therapy often serves as a key strategy towards tumor suppression.Because iterative searching for optimized therapeutic combinations is indeed a daunting,if not preclusive task,we introduce the feedback system control(FSC)scheme,which may serve as a clinically relevant approach,provided a translational approach towards drug delivery is employed.Due to their innate biocompatibility,which has been comprehensively observed,as well as their ability to delivery virtually any type of therapeutic in a sustained fashion due to their unique surface properties,nanodiamonds may serve as a foundation for nanoenabled combinatorial therapy.

关键词： bio-complex system feedback system control drug delivery,nanodiamond combinatorial medicine signaling network nanomedicine

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