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Cited by 949Cellular transport and secretionPI3K/AKT/mTOR signaling in cancerPhagocytosis and Immune Regulation

A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages

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Araki, N, Johnson, M T, Swanson, J A·1996·The Journal of cell biology
DOI 10.1083/jcb.135.5.1249PMC PMC2121091
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Abstract

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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  • Consumption of 4,5-PIP2 by PI3K must contribute to the dissociation of PLCδ-PH-GFP from phagosomes.

    “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

    The Introduction (around p. 1250) says PI3K phosphorylates phosphoinositides to produce phosphatidylinositol (3,4,5)-trisphosphate, and the paper links PI3K activity to completion of phagocytosis. It does not examine PLCδ-PH-GFP or show that PI3K’s consumption of 4,5-PIP2 causes that reporter to dissociate from phagosomes; that causal conclusion goes beyond this source. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • PI3K appears essential for phagocytosis because inhibitors such as wortmannin impair particle engulfment.

    “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

  • The increase in 3,4,5-PIP3 predicted to occur during phagocytosis did not affect the distribution of PLCδ-PH-GFP.

    “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

  • Wortmannin-treated cells fail to internalize particles but nevertheless display marked actin reassembly under adherent RBCs.

    “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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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
DOI
10.1083/jcb.135.5.1249
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
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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