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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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MethodLocalized Biphasic Changes in Phosphatidylinositol-4,5-Bisphosphate at Sites of Phagocytosis
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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).”
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“PI 3-kinase activity is known to be required for effective phagocytosis (Araki et al., 1996; Cox et al., 1999), but its role in maturation has not been investigated.”
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“Thus the acquisition of PI3P through the recruitment and activation of the class 3 phosphatidylinositol 3-kinase, PI3KC3 (also called Vps34), which can directly phosphorylate phosphoinositol, results in the accumulation of EEA1 and the concomitant dissociation of APPLs in maturing early endosomes.”
InfluentialA requirement for phosphatidylinositol 3-kinase in pseudopod extension
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“Although phagocytosis is known to be impaired by wortmannin (4, 11), the effect is directly proportional to the size of the particles used (11) so that phagocytosis of beads with diameters of 3 m proceeds at sufficiently high rates to permit analysis of maturation.”
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“This delicate spatial and temporal coordination is particularly important for the internalization of large particles (119, 164).”
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“In Dictyostelium, macropinocytosis, demonstrated by the formation of circular ruffles or crowns, accounts for most of fluid phase uptake and scanning electron microscopy (SEM) images of the projecting circular ruffles demonstrate the extensive reorganization of the plasma membrane that is required to form macropinosom…”
BackgroundRole of Phospholipids in Endocytosis, Phagocytosis, and Macropinocytosis
Bohdanowicz, M., & Grinstein, S. (2013) · Physiological Reviews · doi:10.1152/physrev.00002.2012 · Cited by 325
“Like CME, macropinocytosis generates fluid-filled vacuoles but, similar to phagocytosis, it requires large-scale actin remodeling and PtdInsP3K activity (17).”
BackgroundInfluentialControl of Phagocytosis by Microbial Pathogens
Uribe‐Querol, E., & Rosales, C. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01368 · Cited by 336
“This lipid then promotes recruitment of other proteins involved in phagosome maturation, including Rab7, a marker of late endosomes (19, 20).”
BackgroundPhagocytosis and the Inflammatory Response
Aderem, A. A. (2003) · The Journal of Infectious Diseases · doi:10.1086/374747 · Cited by 310
“This phenotype resembled that observed when PI-3 kinase was inhibited [11]; and further investigation dem-”
Negative Regulation of Phagocytosis in Macrophages by the CD47-SHPS-1 System
Okazawa, H., Motegi, S., Ohyama, N., Ohnishi, H., Tomizawa, T., Kaneko, Y., Oldenborg, P., Ishikawa, O., & Matozaki, T. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.4.2004 · Cited by 303
“These observations suggest that ligation of Fc R on macrophages promotes phagocytosis not only through activation of downstream signaling molecules such as PI3K or small GTPases of the Rho family (5, 34, 51), but also through dephosphorylation of SHPS-1 and subsequent disruption of its interaction with SHP-1.”
BackgroundActin Depolymerization Disrupts Tight Junctions via Caveolae-mediated Endocytosis
Shen, L., & Turner, J. R. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e04-12-1089 · Cited by 302
“LY294002 inhibits PI-3 kinase and blocks maintenance, maturation and translocation of macropinocytic vesicles (Araki et al., 1996; Murray et al., 2000).”
BackgroundA novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1
Muro, S., Wiewrodt, R. G., Thomas, A., Koniaris, L. S., Albelda, S. Μ., Muzykantov, V. R., & Koval, M. H. (2003) · Journal of Cell Science · doi:10.1242/jcs.00367 · Cited by 302
“Also, uptake of anti-ICAM-1 immunobeads did not require PI3K activity, which is needed for phagocytosis (Araki et al., 1996; Cox et al., 1999), as well as macropinocytosis (West et al.”
BackgroundInfluentialDrug Delivery via Cell Membrane Fusion Using Lipopeptide Modified Liposomes
Yang, J., Bahreman, A., Daudey, G. A., Bussmann, J., Olsthoorn, R. C. L., & Kros, A. (2016) · ACS Central Science · doi:10.1021/acscentsci.6b00172 · Cited by 301
Cox, E. A., Sastry, S. K., & Anna Huttenlocher, A. (2001) · Molecular Biology of the Cell · doi:10.1091/mbc.12.2.265 · Cited by 299
“A macro for transient membrane protrusion was written for Scion Image based on a previously described program (Araki et al., 1996).”
MethodMazumdar, S., Chitkara, D., & Mittal, A. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.02.019 · Cited by 308
Cossart, P., & Lecuit, M. (1998) · The EMBO Journal · doi:10.1093/emboj/17.14.3797 · Cited by 297
“PI-3 kinase has also been implicated in endocytic processes (Araki et al., 1996) and it is possible that some of the components used for endocytosis are also employed by bacterial pathogens to gain entry into host cells.”
BackgroundRegulation of Macropinocytosis by p21-activated Kinase-1
Dharmawardhane, S., Schürmann, A., Sells, M. A., Chernoff, J., Schmid, S. L., & Bokoch, G. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.10.3341 · Cited by 290
“To preferentially focus on the process of macropinocytosis, we used a large 70-kDa dextran molecule in uptake studies (Araki et al., 1996).”
InfluentialDynamin 2 Is Required for Phagocytosis in Macrophages
Gold, E. S., Underhill, D. M., Morrissette, N. S., Guo, J., McNiven, M. A., & Aderem, A. A. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.12.1849 · Cited by 286
“The phagocytic defect induced by dynK44A resembles that seen when PI3K is inhibited in macrophages (29, 30).”
BackgroundResultA contractile activity that closes phagosomes in macrophages
Swanson, J. A., Johnson, M. T., Beningo, K. A., Post, P. L., Mooseker, M. S., & Araki, N. (1999) · Journal of Cell Science · doi:10.1242/jcs.112.3.307 · Cited by 282
Self-citationMarshall, J. G., Booth, J. W., Stambolic, V., Mak, T. W., Balla, T., Schreiber, A. D., Meyer, T., & Grinstein, S. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.7.1369 · Cited by 281
“Prominent among these signals are rapid changes in phosphoinositide metabolism, including the biosynthesis of phosphatidylinositol 3,4,5-trisphosphate (PI[3,4,5]P 3 ) 1 (Araki et al., 1996; Cox et al., 1999) and the hydrolysis of phosphatidylinositol 4,5bisphosphate (PI[4,5]P 2 ) (Azzoni et al.”
BackgroundPhagocytosis and Intracellular Fate of Aspergillus fumigatus Conidia in Alveolar Macrophages
Ibrahim-Granet, O., Philippe, B., Boleti, H., Boisvieux-Ulrich, E., Grenet, D., Stern, M., & Latgé, J. P. (2003) · Infection and Immunity · doi:10.1128/iai.71.2.891-903.2003 · Cited by 277
“It is known that wortmannin irreversibly inhibits the PI 3-kinases required for Fc R- and CR3-mediated phagocytosis (8, 23, 24).”
BackgroundKruth, H. S., Jones, N. L., Huang, W., Zhao, B., Ishii, I., Chang, J., Combs, C. A., Malide, D. A., & Zhang, W.-Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407167200 · Cited by 271
Rho Proteins: Linking Signaling with Membrane Trafficking
Ridley, A. J. (2001) · Traffic · doi:10.1034/j.1600-0854.2001.002005303.x · Cited by 274
“So far, there is no evidence that Rac/Cdc42 are also involved in driving the movement of the phagosome away from the plasma membrane, although interestingly phosphatidylinositide 3-kinase (PI 3-K) appears to act at a later step to regulate internalization but not actin polymerization (22,24).”
BackgroundWest, M. A., Prescott, A. R., Eskelinen, E., Ridley, A. J., & Watts, C. K. W. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00595-9 · Cited by 268
Fitzer‐Attas, C. J., Lowry, M. B., Crowley, M. T., Finn, A. J., Meng, F., DeFranco, A. L., & Lowell, C. A. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.4.669 · Cited by 263
“Treatment of macrophages with inhibitors of PI 3-kinase produces a similar block in phagocytic vesicle closure (15).”
BackgroundMacropinocytosis: regulated coordination of endocytic and exocytic membrane traffic events
Falcone, S., Cocucci, E., Podini, P., Kirchhausen, T. L., Clementi, E., & Meldolesi, J. (2006) · Journal of Cell Science · doi:10.1242/jcs.03238 · Cited by 264
“far been studied in detail are macropinosome sealing, with its concomitant dynamic restructuring of the actin cytoskeleton (West et al., 2004; Lanzetti et al., 2004; Kruth et al., 2005; Araki et al., 1996; Araki et al., 2003; Salter et al., 2004; Swanson et al., 1999; Rupper et al., 2001), and late trafficking of anti…”
BackgroundFc receptor‐mediated phagocytosis requires CDC42 and Rac1
Massol, P., Montcourrier, P., Guillemot, J., & Chavrier, P. (1998) · The EMBO Journal · doi:10.1093/emboj/17.21.6219 · Cited by 254
“The absence of detectable tyrosine phosphorylation of the phosphoinositide 3-kinase (PI 3-kinase) p85 subunit in p72Syk-deficient macrophages is particularly remarkable (Crowley et al., 1997), because chemical inactivation of PI 3-kinase activity by wortmannin (Wtn) also blocks phagocytosis before formation of a seale…”
BackgroundResultInfluentialPhosphatidylinositol-4,5- bis phosphate hydrolysis directs actin remodeling during phagocytosis
Scott, C. C., Dobson, W., Botelho, R. J., Coady-Osberg, N., Chavrier, P., Knecht, D. A., Heath, C. M., Stahl, P. D., & Grinstein, S. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200412162 · Cited by 252
“Treatment with PI3-K inhibitors arrested phagocytosis at an intermediate stage, after actin assembly and partial extension of pseudopodia (Fig. 8, C and D; Araki et al., 1996; Cox et al., 1999; Vieira et al., 2001).”
BackgroundAdenovirus Endocytosis via α v Integrins Requires Phosphoinositide-3-OH Kinase
Li, E., Stupack, D. G., Klemke, R. L., Cheresh, D. A., & Nemerow, G. R. (1998) · Journal of Virology · doi:10.1128/jvi.72.3.2055-2061.1998 · Cited by 250
“The 50% inhibitory concentration was approximately 20 nM, an amount previously shown to inhibit other PI3K-mediated cell functions (1, 23).”
BackgroundSignal transduction during Fc receptor-mediated phagocytosis
García-García, E., & Rosales, C. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.72.6.1092 · Cited by 249
“cytosis [161, 189] and blocks exocytic insertion of membrane”
Backgroundvan der Aa, M. A. E. M., Huth, U., Häfele, S., Schubert, R., Oosting, R. S., Mastrobattista, E., Hennink, W. E., Peschka‐Süss, R., Koning, G. A., & Crommelin, D. J. A. (2007) · Pharmaceutical Research · doi:10.1007/s11095-007-9287-3 · Cited by 242
“For inhibition experiments the cells were first incubated with one of the following inhibitors chlor-promazine (56 m M), LY29004 (50 m M), wortmannin (50 nM), genistein (200 m M) or nocodazole (10 m M) for 60 min or methyl-b -cyclodextrin (164 m M) for 15 min in completed medium prior to addition of polyplexes to the…”
InfluentialHyaluronan Enters Keratinocytes by a Novel Endocytic Route for Catabolism
Tammi, R., Rilla, K. J., Pienimäki, J.-P., MacCallum, D. K., Hogg, M. G., Luukkonen, M., Hascall, V., & Tammi, M. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103481200 · Cited by 241
Rougerie, P., Miskolci, V., & Cox, D. (2013) · Immunological Reviews · doi:10.1111/imr.12118 · Cited by 237
“First, the same phenotype of stalled cup formation has been observed in cells with pharmacological inhibition of PI 3-kinase (PI3K) (35, 59, 66).”
BackgroundMacropinocytosis: A Metabolic Adaptation to Nutrient Stress in Cancer
Recouvreux, M. V., & Commisso, C. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00261 · Cited by 237
“, membrane ruffling and formation of macropinocytic cups), PI3K activity seems to be specifically required for macropinosome closure in tumor cells and macrophages (18, 20, 21).”
BackgroundHirosue, S., Kourtis, I. C., van der Vlies, A. J., Hubbell, J. A., & Swartz, M. A. (2010) · Vaccine · doi:10.1016/j.vaccine.2010.09.077 · Cited by 237
Amyere, M., Payrastre, B., Krause, U., Smissen, P. V. D., Veithen, A., & Courtoy, P. J. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.10.3453 · Cited by 235
“However, whereas it is clear that PI3K controls pseudopod extension, its requirement for their fusion is still controversial, and it may vary with the particle size (Araki et al., 1996; Cox et al., 1999; Swanson et al., 1999).”
BackgroundAntibody-Dependent Cellular Phagocytosis in Antiviral Immune Responses
Tay, M. Z., Wiehe, K. J., & Pollara, J. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00332 · Cited by 242
Systemic Delivery of Oncolytic Viruses: Hopes and Hurdles
Ferguson, M. S., Lemoine, N. R., & Wang, Y. (2012) · Advances in Virology · doi:10.1155/2012/805629 · Cited by 242
Finicle, B. T., Jayashankar, V., & Edinger, A. L. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0048-x · Cited by 241
ER-mediated phagocytosis: a new membrane for new functions
Desjardins, M. (2003) · Nature reviews. Immunology · doi:10.1038/nri1053 · Cited by 230
“Rather, PI3K seems to be involved in the extension of pseudopodia, as shown by the inhibition of phagocytosis and the incomplete pseudopodia formation following cell treatment with the PI3K inhibitors wortmannin and LY294002 (Ref”
BackgroundMcNally, A. K., & Anderson, J. M. (2002) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64882-1 · Cited by 225
Cellular functions of phosphatidylinositol 3-phosphate and FYVE domain proteins
Gillooly, D. J., Simonsen, A., & Stenmark, H. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3550249 · Cited by 229
Loss of Skywalker Reveals Synaptic Endosomes as Sorting Stations for Synaptic Vesicle Proteins
Uytterhoeven, V., Kuenen, S., Kasprowicz, J., Miśkiewicz, K., & Verstreken, P. (2011) · Cell · doi:10.1016/j.cell.2011.02.039 · Cited by 227
Molecular mechanisms of phagocytic uptake in mammalian cells
Groves, E., Dart, A., Covarelli, V., & Caron, E. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-7578-4 · Cited by 238
The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease
Ooms, L. M., Horan, K., Rahman, P., Seaton, G., Gurung, R., Kethesparan, D. S., & Mitchell, C. A. (2009) · Biochemical Journal · doi:10.1042/bj20081673 · Cited by 232
The Rab5 Effector Rabankyrin-5 Regulates and Coordinates Different Endocytic Mechanisms
Schnatwinkel, C., Christoforidis, S., Lindsay, M. R., Uttenweiler‐Joseph, S., Wilm, M. S., Parton, R. G., & Zerial, M. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020261 · Cited by 225
“…et al. 2000), (2) do not promote receptor-mediated endocytosis of transferrin, (3) engulf large amounts of extracellular fluid (Hewlett et al. 1994; Amyere et al. 2000), (4) depend on PI3-K activity (Araki et al. 1996; Zhou et al. 1998), and (5) follow actin rearrangements at the plasma membrane.”
Background
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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