ArticleProceedings of the National Academy of Sciences of the United States of America2007
Ca2+ influx is an essential component of the positive-feedback loop that maintains leading-edge structure and activity in macrophages.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers, 1 of them a synthesis that pooled it.
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Who cites it
95 citing papers in PubMed, 1 synthesis or guideline pooled it.
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- Getting cells into shape by calcium-dependent actin cross-linking proteins.Frontiers in cell and developmental biology · 2023Review
- Anomalous diffusion and asymmetric tempering memory in neutrophil chemotaxis.PLoS computational biology · 2022Article
- The orchestrated signaling by PI3Kα and PTEN at the membrane interface.Computational and structural biotechnology journal · 2022Review
- SLAMF8 Downregulates Mouse Macrophage Microbicidal MechanismsFrontiers in immunology · 2022Article
- Single-molecule studies reveal regulatory interactions between master kinases PDK1, AKT1, and PKC.Biophysical journal · 2021Article
- PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages.Scientific reports · 2021Article
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- Study on the Expansion Dynamics of MDCK Epithelium by Interstitial Flow Using a Traction Force-Measurable Microfluidic Chip.Materials (Basel, Switzerland) · 2021Article
35 more citing papers are in PubMed but not listed here.
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Authors and funding
2 authors.
Funding
Abstract
In migrating eukaryotic cells, phosphatidylinositol 3-kinase (PI3K), filamentous actin (F-actin), and monomeric Rho GTPases are key components of a complex positive-feedback system that maintains and amplifies a phosphatidylinositol-3,4,5-trisphosphate signal at the leading edge of the cell. This lipid signal is required for cell polarization and movement. In leukocytes and Dictyostelium, activation or inhibition of any one of these components leads to the activation or inhibition, respectively, of the others via undefined feedback interactions. The role of Ca(2+) signals in migrating leukocytes is controversial, and there has been no indication that Ca(2+) participates in positive feedback. Here, we demonstrate that an extracellular Ca(2+) influx is required for positive feedback at the leading edge of spontaneously polarized macrophages. Inhibition of extracellular Ca(2+) influx leads to loss of leading-edge PI3K activity, disassembly of F-actin, cessation of ruffling, and decay of chemoattractant signals. Conversely, increasing cytosolic Ca(2+) enhances membrane ruffling, PI3K activity, and F-actin accumulation. Overall, these findings demonstrate that an extracellular Ca(2+) influx is an essential component, together with PI3K and F-actin, of the positive-feedback cycle that maintains leading-edge structure and ruffling activity and that supports the chemoattractant response. Strikingly, the Ca(2+)-sensitive enzyme protein kinase Calpha (PKCalpha) is enriched at the leading edge, and its enrichment is sensitive to blockade of Ca(2+) influx, to inhibition of PI3K activity, and to F-actin depolymerization. These findings support the working hypothesis that a local, leading-edge Ca(2+) signal recruits PKCalpha as a central player in the positive-feedback loop.
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