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A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages
Open accessAbstract
Phosphoinositide 3-kinase (PI 3-kinase) has been implicated in growth factor signal transduction and vesicular membrane traffic. It is thought to mediate the earliest steps leading from ligation of cell surface receptors to increased cell surface ruffling. We show here that inhibitors of PI 3-kinase inhibit endocytosis in macrophages, not by interfering with the initiation of the process but rather by preventing its completion. Consistent with earlier studies, the inhibitors wortmannin and LY294002 inhibited fluid-phase pinocytosis and Fc receptor-mediated phagocytosis, but they had little effect on the receptor-mediated endocytosis of diI-labeled, acetylated, low density lipoprotein. Large solute probes of endocytosis reported greater inhibition by wortmannin than smaller probes did, indicating that macropinocytosis was affected more than micropinocytosis. Since macropinocytosis and phagocytosis are actin-mediated processes, we expected that their inhibition by wortmannin resulted from deficient signaling from macrophage colony-stimulating factor (M-CSF) receptors or Fc receptors to the actin cytoskeleton. However, video microscopy showed cell surface ruffling in wortmannin-treated cells, and increased ruffling after addition of M-CSF or phorbol myristate acetate. Quantitative measurements of video data reported slightly diminished ruffling in wortmannin-treated cells. Remarkably, the ruffles that formed in wortmannin-treated macrophages all receded into the cytoplasm without closing into macropinosomes. Similarly, wortmannin and LY294002 did not inhibit the extension of actin-rich pseudopodia along IgG-opsonized sheep erythrocytes, but instead prevented them from closing into phagosomes. These findings indicate that PI 3-kinase is not necessary for receptor-mediated stimulation of pseudopod extension, but rather functions in the closure of macropinosomes and phagosomes into intracellular organelles.
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“Hence, consumption of 4,5-PIP2 by PI3K must contribute to the dissociation of PLCδ-PH-GFP.”
From Localized Biphasic Changes in Phosphatidylinositol-4,5-Bisphosphate at Sites of Phagocytosis (2000) · cites this paper as Araki et al. 1996
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“This kinase appears to be essential for phagocytosis since inhibitors such as wortmannin impair particle engulfment (Ninomiya et al. 1994; Araki et al. 1996; Cox et al. 1999).”
From Localized Biphasic Changes in Phosphatidylinositol-4,5-Bisphosphate at Sites of Phagocytosis (2000) · cites this paper as Araki et al. 1996
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“The increase in 3,4,5-PIP3 predicted to occur during phagocytosis, based on the reported activation of PI3K (Araki et al. 1996; Cox et al. 1999), did not affect the distribution of PLCδ-PH-GFP.”
From Localized Biphasic Changes in Phosphatidylinositol-4,5-Bisphosphate at Sites of Phagocytosis (2000) · cites this paper as Araki et al. 1996
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“While wortmannin-treated cells fail to internalize particles, they nevertheless display marked actin reassembly under the adherent RBCs (Araki et al. 1996; Cox et al. 1999; and our own observations, not shown).”
From Localized Biphasic Changes in Phosphatidylinositol-4,5-Bisphosphate at Sites of Phagocytosis (2000) · cites this paper as Araki et al. 1996
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“Hence, cells were pre-incubated with a specific inhibitor of PI3-kinase, wortmannin (Araki et al. 1996; Sandgren et al. 2010; Amyere et al. 2000; Kruth et al. 2005) and its effect on hA internalization was examined.”
BackgroundThe Role of Membrane Surface Charge in Phagocytosis
Maxson, M. E., & Grinstein, S. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-40406-2_3 · Cited by 6
Phagocytosis: How the Phagosome Became the Phag-ER-some
Watts, C. K. W. (2002) · Current Biology · doi:10.1016/s0960-9822(02)01163-6 · Cited by 6
Swanson, J. A., & Yoshida, S. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-394447-4.20084-9 · Cited by 6
Self-citationLi, Y., Zhong, J., Lu, X., Ming, C., Zhu, H., Ye, G., Yi, W., Xu, C., & Huang, Y. (2024) · Chemistry of Materials · doi:10.1021/acs.chemmater.4c01543 · Cited by 5
Arai, T., Aiki, Y., & Sato, T. (2022) · Polymer Journal · doi:10.1038/s41428-021-00603-x · Cited by 5
“To elucidate the mechanism of high cell transfection efficiency in RTF, the cellular uptake pathways in RTF were first examined by measuring the luciferase gene expression activity of Huh-7 cells pretreated with endocytosis inhibitors, wortmannin (macropinocytosis inhibitor [23]), MβCD (caveolae-mediated endocytosis i…”
Wolf, A. J., & Underhill, D. M. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1311-4_5 · Cited by 5
Liu, Z., Hu, J. Y., Han, X., Li, L., Niu, H., Zhang, X., Wang, N., Shi, X., Sang, L., Zhang, Q., et al. (2025) · Immunology Letters · doi:10.1016/j.imlet.2025.106990 · Cited by 6
Early biochemical events in leukocyte activation through receptors for IgG
Ortega, E., & Soto‐Cruz, I. (2007) · Signal Transduction · doi:10.1002/sita.200700143 · Cited by 5
Specific Targeting of Engineered Nanoparticles to Activated Macrophages
Chuang, S.-Y., Lin, C., Aljuffali, I. A., & Fang, J. (2015) · Current Nanoscience · doi:10.2174/1573413711666150918190845 · Cited by 5
Egami, Y., & Araki, N. (2018) · Microscopy · doi:10.1093/jmicro/dfx131 · Cited by 5
Self-citationMolecular Mechanisms of Phagosome Formation
Jaumouillé, V., & Grinstein, S. (2017) · ASM Press eBooks · doi:10.1128/9781555819194.ch27 · Cited by 5
Kondomerkos, D. J., Kalamidas, S. A., & Kotoulas, O. B. (2005) · Cell Biochemistry and Function · doi:10.1002/cbf.1205 · Cited by 5
“Insulin is also known to activate phosphatidylinositol-3-kinase, which mediates Fc-receptor-mediated phagocytosis and the formation of endosomes in macrophages.(55,56) Insulin enhances both the phagocytic capacity of macrophages and the production of hydrogen peroxide.”
BackgroundPhosphoinositides in FCgamma receptor signaling
James, W. B. (2006) · Frontiers in bioscience · doi:10.2741/1879 · Cited by 5
Zuliani, J. P., Yamanouye, N., Gutiérrez, J. M., & Teixeira, C. (2024) · Toxicon · doi:10.1016/j.toxicon.2024.107824 · Cited by 4
Human Dendritic Cell Maturation Is Modulated by Leishmania mexicana through Akt Signaling Pathway
González, J. R., Wilkins‐Rodríguez, A. A., & Gutiérrez‐Kobeh, L. (2024) · Tropical Medicine and Infectious Disease · doi:10.3390/tropicalmed9050118 · Cited by 4
“It is known that PI3K is a key regulator of phagocytosis, and Akt is one of the main signal transducers activated by PIP 3 produced during the activation of PI3K [60,61].”
BackgroundUribe‐Querol, E., & Rosales, C. (2024) · Methods in molecular biology · doi:10.1007/978-1-0716-3890-3_3 · Cited by 6
Activators and Inhibitors in Cell Biology Research
Dhaliwal, A. (2013) · Materials and Methods · doi:10.13070/mm.en.3.185 · Cited by 4
Swanson, J. A. (2013) · The Journal of Cell Biology · doi:10.1083/jcb.201310128 · Cited by 4
Self-citationAnalysis of Conventional and Unconventional Trafficking of CFTR and Other Membrane Proteins
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Naik, U., & Harrison, R. E. (2013) · Colloquium Series on Building Blocks of the Cell Cell Structure and Function · doi:10.4199/c00081ed1v01y201304bbc004 · Cited by 3
Heterogeneity in macrophage phagocytosis
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Intracellular Survival and Replication of Legionella Pneumophila within Host Cells
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Kostopoulou, N., Bellou, S., Bagli, E., Μάρκου, Μ., Kostaras, E., Hyvönen, M., Kalaidzidis, Y. L., Papadopoulos, A., Chalmantzi, V., Kyrkou, A., et al. (2021) · Journal of Cell Science · doi:10.1242/jcs.246892 · Cited by 4
Early biochemical events in insulin-stimulated fluid phase endocytosis
Pitterle, D. M., Sperling, R. T., Myers, M. G., White, M. F., & Blackshear, P. J. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.276.1.e94 · Cited by 4
Apical size reduction by macropinocytosis alleviates tissue crowding
Bresteau, E., Suva, E. E., Revell, C. K., Hassan, O. A., Grata, A., Sheridan, J., Mitchell, J., Arvanitis, C., Korobova, F. V., Woolner, S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-60724-2 · Cited by 3
Yang, C., Cheng, Y., Zhang, T., Gebeyew, K., Fischer-Tlustos, A. J., Guan, L. L., Steele, M. A., Tan, Z., & He, Z. (2025) · Animal nutrition · doi:10.1016/j.aninu.2024.11.022 · Cited by 3
African horse sickness virus infects BSR cells through macropinocytosis
Vermaak, E., Conradie, A. M., Maree, F. F., & Theron, J. (2016) · Virology · doi:10.1016/j.virol.2016.07.012 · Cited by 3
Streptococcus pyogenes CAMP factor promotes calcium ion uptake in RAW264.7 cells
Kurosawa, M., Oda, M., Domon, H., Isono, T., Nakamura, Y., Saitoh, I., Hayasaki, H., Yamaguchi, M., Kawabata, S., & Terao, Y. (2018) · Microbiology and Immunology · doi:10.1111/1348-0421.12647 · Cited by 3
“Clathrindependent and -independent endosomes are associated with the PI3K signaling pathway (31, 32).”
BackgroundA tent pole twist on membrane ruffles
Philip, R., & Harrison, R. E. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201810022 · Cited by 3
The Internalization and Intracellular Trafficking of ADCs
Liang, K., Khan, M. S. I., Kalim, M., & Zhan, J. (2023) · Springer eBooks · doi:10.1007/978-981-19-5638-6_4 · Cited by 3
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ATP2B4 is an essential gene for epidermal growth factor‐induced macropinocytosis in A431 cells
Yoshie, S., Kuriyama, M., Maekawa, M., Xu, W. G., Niidome, T., Futaki, S., & Hirose, H. (2024) · Genes to Cells · doi:10.1111/gtc.13118 · Cited by 3
“To this end, we performed a cellular uptake assay using tetramethyl rhodamine-labeled 70 kDa dextran (TMR-dex70), a marker of macropino-somes (Araki et al., 1996), under Ca 2 + -depleted conditions.”
MethodMammalian Host Defenses: Innate and Adaptive Immunity
Georgiev, V. S. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-297-1_38 · Cited by 3
Metadata
- Authors
- Araki, N., Johnson, M. T., & Swanson, J. A.
- Affiliations
- Harvard University (US)
- ORCID
- Venue
- The Journal of cell biology
- Publisher
- Rockefeller University Press
- Published
- 1996-12-01
- Volume
- 135
- Issue
- 5
- Pages
- 1249-1260
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2121091
- OpenAlex
- W2104603012
- Cited by
- 949
- References
- 39
- Citations by year
- 2026: 9 · 2025: 22 · 2024: 25 · 2023: 17 · 2022: 28 · 2021: 37 · 2020: 38 · 2019: 20 · 2018: 39 · 2017: 35 · 2016: 51 · 2015: 26 · 2014: 49 · 2013: 46 · 2012: 48
- FWCI
- 8.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- phosphatidylinositol 3-kinase, macropinocytosis, phagocytosis, macrophages, wortmannin, LY294002, actin cytoskeleton, Fc receptors, macrophage colony-stimulating factor, pseudopod extension, micropinocytosis
- MeSH terms
- Wortmannin, Androstadienes, Animals, Cell Membrane, Cells, Cultured, Chromones, Enzyme Inhibitors, Female, Fluorescent Dyes, Lysosomes, Macrophages, Male, Mice, Inbred C3H, Morpholines, Phagocytosis, Phagosomes, Pinocytosis, Pseudopodia, Receptors, Fc, Tetradecanoylphorbol Acetate, Organelles, Macrophage Colony-Stimulating Factor, Phosphotransferases (Alcohol Group Acceptor), Phosphatidylinositol 3-Kinases, Mice
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