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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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Citations
Cites
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The GTPase dynamin binds to and is activated by a subset of SH3 domains
Gout, I. T., Dhand, R., Hiles, I. D., Fry, M., Panayotou, G., Das, P., Truong, O., Totty, N. F., Hsuan, J. J., Booker, G. W., et al. (1993) · Cell · doi:10.1016/s0092-8674(05)80081-9 · Cited by 557 · cited 1×
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MethodInvolvement of phosphoinositide 3‐kinase in insulin‐ or IGF‐1‐induced membrane ruffling.
Kotani, K., Yonezawa, K., Hara, K., Ueda, H., Kitamura, Y., Sakaue, H., Ando, A., Chavanieu, A., Calas, B., & Grigorescu, F. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06515.x · Cited by 355 · cited 3×
“Nonetheless, a number of cellular processes require PI 3-kinase activity, including mitogenesis (6), membrane ruffling (18, 36), fluid-phase pinocytosis (3, 8), the respiratory burst (2, 22), and lysosomal enzyme sorting (5, 10, 25).”
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Phagocytosis by zippers and triggers
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“Thus, although macropinocytosis and phagocytosis differ in their contents and in the details of signal transduction, they appear mechanistically similar (31).”
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“Nonetheless, a number of cellular processes require PI 3-kinase activity, including mitogenesis (6), membrane ruffling (18, 36), fluid-phase pinocytosis (3, 8), the respiratory burst (2, 22), and lysosomal enzyme sorting (5, 10, 25).”
BackgroundInfluentialSignal transduction and membrane traffic: The PITP/phosphoinositide connection
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“receptor internalization in one study (19), and increased it”
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“M-CSF and PMA stimulate macropinocytosis in macrophages (23, 30).”
BackgroundSelf-citationPhorbol esters stimulate macropinocytosis and solute flow through macrophages
Swanson, J. A. (1989) · Journal of Cell Science · doi:10.1242/jcs.94.1.135 · Cited by 239
Self-citationInvolvement of phosphatidylinositol 3-kinase in Fc gamma receptor signaling.
Ninomiya, N., Hazeki, K., Fukui, Y., Seya, T., Okada, T., Hazeki, O., & Ui, M. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31707-6 · Cited by 210
Thelen, M., Wymann, M. P., & Langen, H. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.11.4960 · Cited by 206
Davidson, H. W. (1995) · The Journal of Cell Biology · doi:10.1083/jcb.130.4.797 · Cited by 198 · cited 3×
“Nonetheless, a number of cellular processes require PI 3-kinase activity, including mitogenesis (6), membrane ruffling (18, 36), fluid-phase pinocytosis (3, 8), the respiratory burst (2, 22), and lysosomal enzyme sorting (5, 10, 25).”
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Self-citationShpetner, H. S., Joly, M., Hartley, D., & Corvera, S. (1996) · The Journal of Cell Biology · doi:10.1083/jcb.132.4.595 · Cited by 181
Signal transduction of phagocytosis
Greenberg, S. (1995) · Trends in Cell Biology · doi:10.1016/s0962-8924(00)88957-6 · Cited by 180 · cited 2×
“Models for Fc receptor function include PI 3-kinase as part of the signal cascade leading to phagocytosis (15, 22).”
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“One possible explanation is that PI 3-kinase has a more significant role in the intracellular membrane traffic that follows internalization (16, 29), and that inhibition of this postendocytic traffic affects rates of fluid-phase endocytosis more than rates of receptor-mediated endocytosis (27).”
BackgroundWortmannin alters the transferrin receptor endocytic pathway in vivo and in vitro.
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“One possible explanation is that PI 3-kinase has a more significant role in the intracellular membrane traffic that follows internalization (16, 29), and that inhibition of this postendocytic traffic affects rates of fluid-phase endocytosis more than rates of receptor-mediated endocytosis (27).”
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Molecular size-fractionation during endocytosis in macrophages.
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“Quantitation of fluorophores was performed as described previously (4, 30).”
BackgroundMethodInfluentialSelf-citationPhosphoinositide 3-kinases and membrane traffic
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“One possible explanation is that PI 3-kinase has a more significant role in the intracellular membrane traffic that follows internalization (16, 29), and that inhibition of this postendocytic traffic affects rates of fluid-phase endocytosis more than rates of receptor-mediated endocytosis (27).”
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“After rinsing again with PBS, the coverslips were mounted on glass slides.”
MethodInfluentialPhosphatidylinositol 3‐kinase regulation of fluid phase endocytosis
Clague, M. J., Thorpe, C., & Jones, A. T. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00576-u · Cited by 76 · cited 2×
“Nonetheless, a number of cellular processes require PI 3-kinase activity, including mitogenesis (6), membrane ruffling (18, 36), fluid-phase pinocytosis (3, 8), the respiratory burst (2, 22), and lysosomal enzyme sorting (5, 10, 25).”
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“Several studies have indicated that PI 3-kinase is not necessary for receptor-mediated endocytosis of soluble ligands (3, 5, 16, 26, 29) (with one exception, reference 19).”
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Acetylated low-density lipoprotein is endocytosed through coated pits by rat peritoneal macrophages
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BackgroundInfluential
Flagged first, then by citations
Cited by
Sorted by citations
Long-Circulating and Target-Specific Nanoparticles: Theory to Practice
Moghimi, S. M., Hunter, A. C., & Murray, J. C. (2001) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01494-7 · Cited by 3,521
“Cross-linking of FcgRI and FcgRII increases the activity of PI-3 kinase but FcgR-mediated phagocytosis is prevented by PI 3-kinase inhibitors wortmannin and LY294002 (Araki et al., 1996).”
Mechanisms of phagocytosis in macrophages
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Alternative Activation of Macrophages: An Immunologic Functional Perspective
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Routes and mechanisms of extracellular vesicle uptake
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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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