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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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“PI3K inhibitors [97] and filamentous actin depolymerizing agents can block phagocytosis but their inhibitory effects are not restricted to this pathway [82].”
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“the presence of PI3K inhibitors, indicating that this family of enzymes is vital for the size-dependent progression to the later stages of phagocytosis [14, 49].”
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Enhancement of fcgamma receptor-mediated phagocytosis by transforming mutants of Cbl.
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Involvement of protein kinases on the process of erythrophagocytis by Entamoeba histolytica
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“previous studies carried out in other cells showing that PI 3-kinase is required for maximal pseudopod extension and closure of the phagocytic vacuole during phagocytosis, but it seems to be dispensable for the initial phases of actin polymerization (Araki et al., 1996; Cox et al., 1999).”
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“In macrophages, baby hamster kidney cells, and bipolar cell terminals, it was demonstrated that bulk retrieval is dependent on the activity of a phosphatidylinositol-3-phosphate kinase (2, 13, 22) and can be blocked by LY-294002, a phosphatidylinositol 3-phosphate kinase inhibitor.”
BackgroundDissection of the Interplay between Class I PI3Ks and Rac Signaling in Phagocytic Functions
Costa, C., Germena, G., & Hirsch, E. (2010) · The Scientific World JOURNAL · doi:10.1100/tsw.2010.178 · Cited by 18
“While this PI3K activity has no role in the polymerization of F-actin at the phagocytic cup[60,61], it is involved in membrane extension around target particles as well as in the closure of pseudopodia into phagosomes[58,60].”
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Baritussio, A., Alberti, A., Armanini, D., Meloni, F., & Bruttomesso, D. (2000) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.2000.279.1.l91 · Cited by 18
“5, and fluorescence of the lysate was measured with a spectrofluorimeter (PerkinElmer RS 3B) with excitation at 495 nm and emission at 514 nm (3).”
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“As shown in Table 1, inhibition of PI-3K, which has been associated with complete prevention of the formation of macropinosome-like structures (Araki et al., 1996), significantly reduced the uptake of M.”
ResultMacropinocytosis is decreased in diabetic mouse macrophages and is regulated by AMPK
Guest, C. B., Chakour, K. S., & Freund, G. G. (2008) · BMC Immunology · doi:10.1186/1471-2172-9-42 · Cited by 18
“Macropinocytosis is characterized by the uptake of fluid through relatively large vacuoles (up to 5 microns) [2,3].”
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“The PI3K/Akt pathway is a key signal transduction pathway involved in the process of phagocytosis.(18,32,33) Studies have shown that Akt activation was increased during phagocytosis.”
BackgroundThe granulocyte orphan receptor CEACAM4 is able to trigger phagocytosis of bacteria
Tascon, J. D., Adrian, J., Kopp, K., Scholz, P., Tschan, M. P., Kuespert, K., & Hauck, C. R. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.2ab0813-449rr · Cited by 18
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Role for phosphoinositide 3-kinase in FcγRIIA-induced platelet shape change
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“It has been shown that PI3-kinase is not necessary for actin assembly and Arp2/3 complex recruitment during Fc RIIA-mediated phagocytosis (1, 27).”
BackgroundCellular Regulation of Macropinocytosis
Wu, Y., Hu, X., Wei, Z. J., & Lin, Q. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25136963 · Cited by 17
“…H + -ATPase inhibitor Bafilomycin A1 [66,97], the PAK1 inhibitor IPA-3 [22], the actin polymerization inhibitors [31], the PI3K inhibitors [25], the DOCK1 inhibitor TBOPP [99] and the lysosomal inhibitor HCQ [64] are all able to inhibit macropinocytosis and have been used for cancer…”
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“The interactions between polyplexes and cell membranes were examined by treating the cells with different chemical inhibitors: wortmannin for macropinocytosis; 25 chlorpromazine for clathrin-mediated endocytosis; 26 and genistein for caveolae-mediated endocytosis.”
Underhill, D. M., & Ozinsky, A. (2002) · Cited by 17
Ultrastructure of Adenovirus Keratitis
Mukherjee, S., Zhou, X., Rajaiya, J., & Chodosh, J. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-15635 · Cited by 16
Kang, S. C., Koo, H. J., Park, S., Lim, J. D., Kim, Y., Kim, T., Namkoong, S., Jang, K., Pyo, S., Jang, S., et al. (2013) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2013.03.017 · Cited by 16
Nellimarla, S., Baid, K., Loo, Y., Gale, M., Bowdish, D. M. E., & Mossman, K. L. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1501028 · Cited by 16
“Because PI3K has been implicated in regulating endocytosis, cell adhesion, and intracellular membrane trafficking in macrophages (41, 42), we quantified extracellular dsRNA entry in the absence of PI3K activity.”
BackgroundAvaritt, B. R., & Swaan, P. W. (2015) · Molecular Pharmaceutics · doi:10.1021/mp500765e · Cited by 16
TMEM55a localizes to macrophage phagosomes to downregulate phagocytosis
Morioka, S., Nigorikawa, K., Okada, E., Tanaka, Y., Kasuu, Y., Yamada, M., Kofuji, S., Takasuga, S., Nakanishi, H., Sasaki, T., et al. (2018) · Journal of Cell Science · doi:10.1242/jcs.213272 · Cited by 18
“, 2008), which is followed by its immediate disassembly induced by PtdIns(4,5)P2 disappearance for cup closure (Araki et al., 1996; Schlam et al., 2015).”
BackgroundInfluentialLundberg, P., & Langel, Ü. (2006) · International Journal of Peptide Research and Therapeutics · doi:10.1007/s10989-005-9007-y · Cited by 16
“PI 3-kinase is thought to be involved in fluid phase endocytosis (Clague et al., 1995), like macropinocytosis (Araki et al., 1996) and early endosome fusion (Jones and Clague, 1995), rather than in receptor mediated endocytosis (Backer, 2000).”
BackgroundPMA activation of macrophages alters macrophage metabolism of aggregated LDL
Huang, W., Ishii, I., Zhang, W., Sonobe, M., & Kruth, H. S. (2002) · Journal of Lipid Research · doi:10.1194/jlr.m100436-jlr200 · Cited by 16
“Wortmannin has been shown to inhibit both macropinocytosis and phagocytosis in macrophages, suggesting that transfer of AgLDL from SCCs to lysosomes may involve one of these two endocytic processes ( 35 ).”
BackgroundEffective Cell Transfection in An Ultrasonically Levitated Droplet for Sustainable Technology
Arai, T., Sato, T., & Matsubara, T. (2022) · Advanced Science · doi:10.1002/advs.202203576 · Cited by 15
Mannose receptor (MRC1) mediates uptake of dextran by bone marrow–derived macrophages
Wollman, J. W., Wanniarachchi, K. N., Pradhan, B., Huang, L., Kerkvliet, J. G., Hoppe, A. D., & Thiex, N. W. (2024) · Molecular Biology of the Cell · doi:10.1091/mbc.e24-08-0355 · Cited by 22
“Pretreatment of cells with the PI3K inhibitor LY294002 caused a large decrease in Lucifer yellow uptake and a minor effect on dextran uptake (Figure 4F), consistent with inhibition of pinocy-tosis but not MRC1-mediated endocytosis of dextran (Araki et al. , 1996; Quinn et al. , 2021).”
Leukotrienes Produced in Allergic Lung Inflammation Activate Alveolar Macrophages
Silva, R. C., Landgraf, M. A., Hiyane, M. I., Pacheco‐Silva, Á., Câmara, N. O. S., & Landgraf, R. G. (2010) · Cellular Physiology and Biochemistry · doi:10.1159/000320555 · Cited by 15
Roettger, Y., Zerr, I., Dodel, R. C., & Bach, J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067743 · Cited by 15
“Wortmannin is a potent inhibitor of phosphatidylinositol 3kinase (PI3K) [25] and inhibits actin-dependent endocytosis, fluidphase pinocytosis and phagocytosis [26].”
BackgroundLu, S. M., & Fairn, G. D. (2018) · Traffic · doi:10.1111/tra.12576 · Cited by 15
Peruzzi, G., Masilamani, M., Borrego, F., & Coligan, J. E. (2008) · Immunologic Research · doi:10.1007/s12026-008-8072-7 · Cited by 15
“Thus, beside the size of the pinocytic vesicles, micropinocytosis is distinguished from macropinocytosis by its PI3K and actin independency [66], and resistance to AlF4 - and amiloride exposure.”
Amplification of PIP3 signalling by macropinocytic cups
Kay, R. R., Williams, T. D., & Paschke, P. (2018) · Biochemical Journal · doi:10.1042/bcj20170785 · Cited by 15
Moeenrezakhanlou, A., Nandan, D., Shephard, L., & Reiner, N. E. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.1106681 · Cited by 16
“In particular, the 3 -phosphoinositide metabolites produced by the PI-3K family of lipid kinases are known to be involved in regulating numerous monocyte activities including phagocytosis [3], activation of the phagocyte oxidase [4], and the production of cytokines downstream of TLRs [5–7] to name a few.”
BackgroundKelley, V. A., & Schorey, J. S. (2004) · Cellular Microbiology · doi:10.1111/j.1462-5822.2004.00415.x · Cited by 15
“However, the disadvantage of using PI-3 kinase inhibitors is that the effects are not limited to endosomes and phagosomes but instead may inhibit all aspects associated with PtdIns-3-P or PI(3,4,5)P3 formation, including phagocytosis (Araki et al., 1996).”
BackgroundFernando, L. P., Kandel, P. K., Ackroyd, P. C., & Christensen, K. (2012) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-012-6441-5 · Cited by 15
“Since PI3K is required for spontaneous cell surface ruffling that is an integral part of macropinocytosis [47], inhibition of uptake in the presence of wortmannin and LY294002 indicates that nanoparticles enter the cell through macropinocytosis.”
BackgroundHisatsune, A., Kawasaki, M., Nakayama, H., Mikami, Y., Miyata, T., Isohama, Y., Katsuki, H., & Kim, K. C. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.08.059 · Cited by 15
Labeling of Endocytic Vesicles Using Fluorescent Probes for Fluid-Phase Endocytosis
Araki, N. (2006) · Elsevier eBooks · doi:10.1016/b978-012164730-8/50093-9 · Cited by 15
Self-citationGillette, D. D., Tridandapani, S., & Butchar, J. P. (2014) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2014.00018 · Cited by 14
“The cellular processes mediated by PI3K include phagocytosis (Araki et al., 1996), autophagy (Petiot et al., 2000), cytokine production (Parsa et al., 2006), and oxidative burst (Chen et al., 2003; Hoyal et al., 2003).”
BackgroundPinheiro, C. S., Monteiro, A. P. T., Dutra, F. F., Bozza, M. T., Peters-Golden, M. L., Benjamim, C. F., & Canetti, C. D. A. (2017) · Mediators of Inflammation · doi:10.1155/2017/2086840 · Cited by 15
“Sheep red blood cells (RBCs) were opsonized with a subagglutinating concentration of IgG rabbit antisheep erythrocyte antibody (Cappel Organon Teknika, Durham, NC) as previously described [29].”
MethodNakagawa, Y., Arafiles, J. V. V., Kawaguchi, Y., Nakase, I., Hirose, H., & Futaki, S. (2022) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.2c00113 · Cited by 14
Benayas, E., Espinosa, A., Portolés, M. T., Sol, V. V., Morales, M. P., & Serrano, M. C. (2023) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.3c02729 · Cited by 14
“56,57 Based on the results described above, 0.05 mg Fe mL − 1 and 2 h of exposure were selected as the optimal conditions to maximize internalization with the highest preservation of cell viability.”
InfluentialKan‐o, K., Matsumoto, K., Asai, Y., Fukuyama, S., Hamano, S., Seki, N., Nakanishi, Y., & Inoue, H. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.04.082 · Cited by 14
Leddy, O. K., Ogongo, P., Huffaker, J., Gan, M., Milligan, R., Mahmud, S., Ni, H. M., Yuki, Y., Bobosha, K., Wassie, L., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adw9184 · Cited by 16
Jiang, X., Fu, J., Zhong, J., Li, X., Wang, H., Zhong, S., Wei, Y., Zhao, X., Chen, X., Zhou, Y., et al. (2021) · ACS Macro Letters · doi:10.1021/acsmacrolett.1c00236 · Cited by 13
Phosphoinositide 3-kinase at the crossroad between endocytosis and signaling of cytokine receptors
Sauvonnet, N. (2013) · Communicative & Integrative Biology · doi:10.4161/cib.24243 · Cited by 13
Lu, Y., Cao, L., Egami, Y., Kawai, K., & Araki, N. (2016) · Microscopy · doi:10.1093/jmicro/dfv376 · Cited by 13
Self-citationAcute Kidney Injury Reduces Phagocytic and Microbicidal Capacities of Alveolar Macrophages
Silva, R. C., Landgraf, M. A., Corrêa-Costa, M., Semedo, P., Cenedeze, M. A., Pacheco‐Silva, Á., Landgraf, R. G., & Câmara, N. O. S. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000343359 · Cited by 13
Whitman, S. C., Daugherty, A., & Post, S. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001797200 · Cited by 13
Kovalenko, A., Sanin, A., Kosmas, K., Zhang, L., Wang, J., Akl, E. W., Giannikou, K., Probst, C. K., Hougard, T. R., Rue, R. W., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-2218 · Cited by 13
Isobe, I., Yanagisawa, K., & Michikawa, M. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00237.x · Cited by 13
“Although 500 nm of wortmannin is a relatively high concentration with regard to its speci®city to PI(3)K, LY294002 which has been reported to show little or no inhibition to other enzymes affected by wortmannin, such as phosphatidylinositol 4-kinase, myosin light chain kinase or phospholipase A2 (Vlahos et al. 1994; A…”
BackgroundYang, Q., Li, L., Zhu, X. D., Sun, W. Y., Zhou, Z., & Huang, Y. (2015) · RSC Advances · doi:10.1039/c4ra16085a · Cited by 12
Macropinocytosis mediates resistance to loss of glutamine transport in triple-negative breast cancer
Wahi, K., Freidman, N., Wang, Q., Devadason, M., Quek, L., Pang, A., Lloyd, L., Larance, M., Zanini, F., Harvey, K., et al. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00271-6 · Cited by 13
“This also involves the recruitment of sorting nexin proteins (SNX1, 5, 9 and 33), Rac1 and Pak1 to the macropinosomes (Finicle et al, 2018; Zhang and Commisso, 2019; Lim and Gleeson, 2011).”
Neupane, R., Malla, S., Karthikeyan, C., Asbhy, C. R., Boddu, S. H. S., Babu, R. J., & Tiwari, A. K. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.125356 · Cited by 12
Kwong, C., Gilman‐Sachs, A., & Beaman, K. D. (2013) · OncoImmunology · doi:10.4161/onci.22978 · Cited by 12
“To determine if a2NTD enhances macropinocytosis, PBMCs were incubated with a fluid-phase macropinocytosis marker, 10 kDa neutral dextran, in combination with increasing concentrations of a2NTD. Consistent with the observation of others, 27 dextran was efficiently taken up by macropinocytosis at 37°C.”
MethodPI3K and NADPH oxidase: a class act
Kennedy, A. D., & DeLeo, F. R. (2008) · Blood · doi:10.1182/blood-2008-09-179135 · Cited by 12
Bandyopadhyay, C., Veettil, M. V., Dutta, S., & Chandran, B. (2014) · Journal of Virology · doi:10.1128/jvi.01674-14 · Cited by 12
Essential cues of engineered polymeric materials regulating gene transfer pathways
Islam, M. A., Park, T., Firdous, J., Li, H.-S., Jiménez-Pérez, Z. E., Lim, M., Choi, J.-W., Yun, C., & Cho, C. (2022) · Progress in Materials Science · doi:10.1016/j.pmatsci.2022.100961 · Cited by 12
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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