12
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Computational investigation of sphingosine kinase 1 (SphK1) and calcium dependent ERK1/2 activation downstream of VEGFR2 in endothelial cells

      research-article
      * ,
      PLoS Computational Biology
      Public Library of Science

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Vascular endothelial growth factor (VEGF) is a powerful regulator of neovascularization. VEGF binding to its cognate receptor, VEGFR2, activates a number of signaling pathways including ERK1/2. Activation of ERK1/2 is experimentally shown to involve sphingosine kinase 1 (SphK1) activation and its calcium-dependent translocation downstream of ERK1/2. Here we construct a rule-based computational model of signaling downstream of VEGFR2, by including SphK1 and calcium positive feedback mechanisms, and investigate their consequences on ERK1/2 activation. The model predicts the existence of VEGF threshold in ERK1/2 activation that can be continuously tuned by cellular concentrations of SphK1 and sphingosine 1 phosphate (S1P). The computer model also predicts powerful effects of perturbations in plasma and ER calcium pump rates and the current through the CRAC channels on ERK1/2 activation dynamics, highlighting the critical role of intracellular calcium in shaping the pERK1/2 signal. The model is then utilized to simulate anti-angiogenic therapeutic interventions targeting VEGFR2-ERK1/2 axis. Simulations indicate that monotherapies that exclusively target VEGFR2 phosphorylation, VEGF, or VEGFR2 are ineffective in shutting down signaling to ERK1/2. By simulating therapeutic strategies that target multiple nodes of the pathway such as Raf and SphK1, we conclude that combination therapy should be much more effective in blocking VEGF signaling to EKR1/2. The model has important implications for interventions that target signaling pathways in angiogenesis relevant to cancer, vascular diseases, and wound healing.

          Author summary

          Vascular endothelial growth factor (VEGF) signaling is a potent regulator of angiogenesis, the growth and development of new vessels out of a preexisting vascular network. Angiogenesis requires enhanced survival, proliferation, and motility of the vascular endothelial cells. Crucial signaling endpoints in VEGF-mediated angiogenic response include elevation in intracellular calcium and the activation of the proteins ERK1 and 2 (ERK1/2). In this study, we have developed a novel computer model for the activation of ERK1/2 and calcium downstream of VEGF receptor type 2 (VEGFR2). Our model is the first of its kind to incorporate and investigate the consequences of calcium elevation and the role of a cellular lipid modifier known as sphingosine kinase 1 (SphK1). We also utilize the model to simulate therapeutic strategies targeting VEGF signaling to ERK1/2 indicating inefficiency of single therapies known as tyrosine kinase inhibitors (TKI) that target receptor phosphorylation. Computer simulations indicate that combination therapy is essential for effective blockade of this important pathway. Our results have important implications for human diseases such as cancer where plethora of anti-VEGF therapies are currently employed. Overall, our computer model sheds new light on a complex feedback involving SphK1 and calcium that radically alters the response of cells to VEGF.

          Related collections

          Most cited references55

          • Record: found
          • Abstract: found
          • Article: not found

          NIH Image to ImageJ: 25 years of image analysis.

          For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Angiogenesis in life, disease and medicine.

            The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and blindness. Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A methodology for performing global uncertainty and sensitivity analysis in systems biology.

              Accuracy of results from mathematical and computer models of biological systems is often complicated by the presence of uncertainties in experimental data that are used to estimate parameter values. Current mathematical modeling approaches typically use either single-parameter or local sensitivity analyses. However, these methods do not accurately assess uncertainty and sensitivity in the system as, by default, they hold all other parameters fixed at baseline values. Using techniques described within we demonstrate how a multi-dimensional parameter space can be studied globally so all uncertainties can be identified. Further, uncertainty and sensitivity analysis techniques can help to identify and ultimately control uncertainties. In this work we develop methods for applying existing analytical tools to perform analyses on a variety of mathematical and computer models. We compare two specific types of global sensitivity analysis indexes that have proven to be among the most robust and efficient. Through familiar and new examples of mathematical and computer models, we provide a complete methodology for performing these analyses, in both deterministic and stochastic settings, and propose novel techniques to handle problems encountered during these types of analyses.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                PLoS Comput. Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, CA USA )
                1553-734X
                1553-7358
                8 February 2017
                February 2017
                : 13
                : 2
                : e1005332
                Affiliations
                [001]Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America
                University of Pennsylvania, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                • Conceived and designed the experiments: HB ASP.

                • Performed the experiments: HB.

                • Analyzed the data: HB ASP.

                • Contributed reagents/materials/analysis tools: HB ASP.

                • Wrote the paper: HB ASP.

                Article
                PCOMPBIOL-D-16-01119
                10.1371/journal.pcbi.1005332
                5298229
                28178265
                11198cfc-4132-4969-9111-1385d5f58191
                © 2017 Bazzazi, Popel

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 July 2016
                : 23 December 2016
                Page count
                Figures: 5, Tables: 0, Pages: 23
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01HL101200
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01CA138264
                Award Recipient :
                This work was supported by the National Institutes of Health grants R01HL101200 (ASP) and R01CA138264 (ASP) www.nih.gov. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                VEGF signaling
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Cell Signaling
                Calcium Signaling
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Phosphorylation
                Biology and Life Sciences
                Biophysics
                Ion Channels
                Calcium Channels
                Physical Sciences
                Physics
                Biophysics
                Ion Channels
                Calcium Channels
                Biology and Life Sciences
                Physiology
                Electrophysiology
                Ion Channels
                Calcium Channels
                Medicine and Health Sciences
                Physiology
                Electrophysiology
                Ion Channels
                Calcium Channels
                Biology and Life Sciences
                Physiology
                Electrophysiology
                Neurophysiology
                Ion Channels
                Calcium Channels
                Medicine and Health Sciences
                Physiology
                Electrophysiology
                Neurophysiology
                Ion Channels
                Calcium Channels
                Biology and Life Sciences
                Neuroscience
                Neurophysiology
                Ion Channels
                Calcium Channels
                Biology and Life Sciences
                Biochemistry
                Proteins
                Ion Channels
                Calcium Channels
                Biology and Life Sciences
                Physiology
                Cardiovascular Physiology
                Angiogenesis
                Medicine and Health Sciences
                Physiology
                Cardiovascular Physiology
                Angiogenesis
                Biology and Life Sciences
                Developmental Biology
                Angiogenesis
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Epithelial Cells
                Endothelial Cells
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Endothelial Cells
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Epithelium
                Epithelial Cells
                Endothelial Cells
                Biology and Life Sciences
                Biochemistry
                Proteins
                Intracellular Receptors
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Intracellular Receptors
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

                Quantitative & Systems biology
                Quantitative & Systems biology

                Comments

                Comment on this article