PLoS computational biology, 2020-04, Vol.16 (4), p.e1007708-e1007708
2020
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- Autor(en) / Beteiligte
- Titel
- Mechanistic models of PLC/PKC signaling implicate phosphatidic acid as a key amplifier of chemotactic gradient sensing
- Ist Teil von
- PLoS computational biology, 2020-04, Vol.16 (4), p.e1007708-e1007708
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Chemotaxis of fibroblasts and other mesenchymal cells is critical for embryonic development and wound healing. Fibroblast chemotaxis directed by a gradient of platelet-derived growth factor (PDGF) requires signaling through the phospholipase C (PLC)/protein kinase C (PKC) pathway. Diacylglycerol (DAG), the lipid product of PLC that activates conventional PKCs, is focally enriched at the up-gradient leading edge of fibroblasts responding to a shallow gradient of PDGF, signifying polarization. To explain the underlying mechanisms, we formulated reaction-diffusion models including as many as three putative feedback loops based on known biochemistry. These include the previously analyzed mechanism of substrate-buffering by myristoylated alanine-rich C kinase substrate (MARCKS) and two newly considered feedback loops involving the lipid, phosphatidic acid (PA). DAG kinases and phospholipase D, the enzymes that produce PA, are identified as key regulators in the models. Paradoxically, increasing DAG kinase activity can enhance the robustness of DAG/active PKC polarization with respect to chemoattractant concentration while decreasing their whole-cell levels. Finally, in simulations of wound invasion, efficient collective migration is achieved with thresholds for chemotaxis matching those of polarization in the reaction-diffusion models. This multi-scale modeling framework offers testable predictions to guide further study of signal transduction and cell behavior that affect mesenchymal chemotaxis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1553-7358, 1553-734XeISSN: 1553-7358DOI: 10.1371/journal.pcbi.1007708Titel-ID: cdi_plos_journals_2403774268
- Format
- –
- Schlagworte
- Acids, Alanine, Analysis, Animals, Biology and Life Sciences, Cell migration, Cellular signal transduction, Chemotaxis, Chemotaxis - physiology, Computer simulation, Diacylglycerol, Diffusion, Diglycerides, Diglycerides - metabolism, Embryogenesis, Embryonic growth stage, Engineering and Technology, Feedback, Feedback loops, Fibroblasts, Fibroblasts - metabolism, Funding, Growth factors, Humans, Influence, Intracellular Signaling Peptides and Proteins - metabolism, Kinases, Leukocyte migration, Lipids, MARCKS protein, Mechanical properties, Medicine and Health Sciences, Membrane Proteins - metabolism, Mesenchyme, Models, Theoretical, Multiscale analysis, Myristoylated Alanine-Rich C Kinase Substrate - metabolism, Partial differential equations, Phosphatidic acid, Phosphatidic Acids - metabolism, Phosphatidic Acids - physiology, Phospholipase, Phospholipase C, Phospholipase D, Phospholipase D - metabolism, Phospholipases, Phospholipids, Phosphorylation, Platelet-derived growth factor, Platelet-Derived Growth Factor - metabolism, Polarization, Polymerization, Protein kinase C, Protein Kinase C - metabolism, Protein Kinase C - physiology, Protein kinases, Regulators, Signal transduction, Signal Transduction - physiology, Signaling, Simulation, Social Sciences, Substrates, Type C Phospholipases - metabolism, Type C Phospholipases - physiology, Wound healing