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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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BackgroundMutations in human dynamin block an intermediate stage in coated vesicle formation
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Phosphoinositides and engulfment
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“In macrophages, PI 3-kinase inhibitors do not affect cell surface ruffling or circular ruffle formation, but instead inhibit cup closure into macropinosomes (Araki et al., 1996).”
BackgroundInfluentialSelf-citationAccumulation of iron oxide nanoparticles by cultured primary neurons
Petters, C., & Dringen, R. (2014) · Neurochemistry International · doi:10.1016/j.neuint.2014.12.005 · Cited by 39
“…MP Li et al., 2013; Shi et al., 2013 10 μM 6 ± 0 356 ± 1 96 ± 0 2 EIPA MP Iversen et al., 2012 25 μM 7 ± 5 342 ± 19 93 ± 7 2 Methyl-β-cyclodextrin CvME Le et al., 2002 2.5 mM 12 ± 4 367 ± 15 100 ± 6 2 Wortmannin MP Araki et al., 1996 100 nM 14 ± 14 340 ± 3 92 ± 1 2 Cells were incubated for 30 min…”
InfluentialTachado, S. D., Samrakandi, M. M., & Cirillo, J. D. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003324 · Cited by 39
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“Phagocytosis has been shown to be dependent on PI 3-kinase activity [Araki et al., 1996], which converts PI(4,5)P2 to PI(3,4,5)P3, and expression of the GFP-Akt-PH domain probe revealed a distinct enhancement within waves (Supporting Information Fig.”
BackgroundResultRittig, M. G., Jagoda, J. C., Wilske, B., Murgia, R., Cinco, M., Repp, R., Burmester, G. R., & Krause, A. (1998) · Infection and Immunity · doi:10.1128/iai.66.2.627-635.1998 · Cited by 39
“phatidylinositol 3-kinase by wortmannin (2), phospholipase A2 by 4BPB (26), geranylgeranyltransferase I by AGGC (9), the Na(1)/H(1) antiport by DMA (22), and the V-type H(1)-ATPases by bafilomycin A1 (22).”
BackgroundRegulation of tyrosine phosphorylation in macrophage phagocytosis and chemotaxis
Park, H., Ishihara, D., & Cox, D. (2011) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2011.02.019 · Cited by 38
CYRI-A limits invasive migration through macropinosome formation and integrin uptake regulation
Le, H. A., Yelland, T., Paul, N. R., Fort, L., Nikolaou, S., Ismail, S., & Machesky, L. M. (2021) · The Journal of Cell Biology · doi:10.1083/jcb.202012114 · Cited by 38
“This fits in with a previous observation that LY294002 blocked the resolution of macropinocytic cups (Araki et al., 1996).”
BackgroundResultCharacterization of the Cell-penetrating Properties of the Epstein-Barr Virus ZEBRA trans-Activator
Rothe, R., Liguori, L., Villegas-Méndez, A., Marques, B., Grünwald, D., Drouet, E., & Lenormand, J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.101550 · Cited by 48
Increase in Phagocytosis after Geldanamycin Treatment or Heat Shock: Role of Heat Shock Proteins
Vega, V. L., & De Maio, A. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.8.5280 · Cited by 41
“Phagocytosis requires actin rearrangement (12) and activation of Src and Syk tyrosine kinases (13, 14), Rho GTPases (15), PI3K, and phospholipases A2, C, and D (16–18).”
BackgroundThe cell surface environment for pathogen recognition and entry
Stow, J. L., & Condon, N. D. (2016) · Clinical & Translational Immunology · doi:10.1038/cti.2016.15 · Cited by 39
Hu, B., Punturieri, A., Todt, J. C., Sonstein, J., Polak, T., & Curtis, J. L. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.71.5.881 · Cited by 37
“This is particularly likely for PI-3K inhibition, which has been shown previously to block phagosome closure during FcR-mediated phagocytosis [17, 26].”
BackgroundDelivery of the CSF-1R to the lumen of macropinosomes promotes its destruction in macrophages
Lou, J., Low-Nam, S. T., Kerkvliet, J. G., & Hoppe, A. D. (2014) · Journal of Cell Science · doi:10.1242/jcs.154393 · Cited by 36
“CSF-1 potently stimulates macropinocytosis in macrophages in a phosphoinositide 3-kinase (PI3K)- and Rac1-dependent manner (Araki et al., 1996; Boocock et al., 1989; Fujii et al., 2013; Racoosin and Swanson, 1992).”
BackgroundSequential recruitment of Rab GTPases during early stages of phagocytosis
Yeo, J. C., Wall, A. A., Luo, L., & Stow, J. L. (2016) · Cellular Logistics · doi:10.1080/21592799.2016.1140615 · Cited by 37
Dorsal ruffles enhance activation of Akt by growth factors
Yoshida, S., Pacitto, R., Sesi, C., Kotula, L., & Swanson, J. A. (2018) · Journal of Cell Science · doi:10.1242/jcs.220517 · Cited by 35
“Conversely, the formation of CDR or closure of cups into macropinosomes requires PI3K (Wymann and Arcaro, 1994, Araki et al., 1996, Hooshmand-Rad et al., 1997, Valdivia et al., 2017), which suggests that CDR and macropinocytic cups are self-organized structures that require PIP3 for complete…”
BackgroundSelf-citationRegulation of the Endosomal SNARE Protein Syntaxin 7 by Colony-Stimulating Factor 1 in Macrophages
Achuthan, A. A., Masendycz, P. J., Lopez, J. A., Nguyen, T. U., James, D. E., Sweet, M. J., Hamilton, J. A., & Scholz, G. M. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00220-08 · Cited by 36
“PI 3-kinase activity is required for a range of vesicular trafficking processes in macrophages (4, 36, 58).”
BackgroundDokainish, H., Gavicherla, B., Shen, Y., & Ireton, K. (2007) · Cellular Microbiology · doi:10.1111/j.1462-5822.2007.00976.x · Cited by 35
“…(Ninomiya et al., 1994; Cox et al., 1999) and its lipid products accumulate on phagocytic cups (Marshall et al., 2001), p85-p110 is required for steps that follow localized actin polymerization, such as pseudopod extension (Cox et al., 1999) and/or phagosome sealing (Araki et al., 1996).”
BackgroundByekova, Y. A., Powell, R. R., Welter, B. H., & Temesvari, L. A. (2009) · Infection and Immunity · doi:10.1128/iai.00719-09 · Cited by 37
“GFP-labeled PH domains have demonstrated that PIP3 regulates phagocytosis in neutrophils (7), macrophages (1), and a nonpathogenic soil amoeba, Dictyostelium discoideum (9, 13).”
BackgroundCorbett-Nelson, E. F., Mason, D. Y., Marshall, J. G., Collette, Y., & Grinstein, S. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200605044 · Cited by 36
“As reported earlier (Araki et al., 1996; Cox et al., 1999), treatment with inhibitors of this kinase arrested the development of phagosomes at an intermediate stage, where cup formation is evident but sealing is impaired, LIPID MOBILITY DURING PHAGOCYTOSIS • CORBETT-NELSON ET AL.”
BackgroundResultKang, T., Park, C., & Lee, B.-J. (2016) · Archives of Pharmacal Research · doi:10.1007/s12272-016-0847-0 · Cited by 35
“This inhibitor that blocks the action of phosphoinositide 3-kinase is the key regulator in macropinocytosis (Araki et al. 1996; Khandelwal et al. 2010).”
BackgroundFunction of small GTPases in Dictyostelium macropinocytosis
Williams, T. D., Paschke, P., & Kay, R. R. (2018) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2018.0150 · Cited by 34
Arpin is critical for phagocytosis in macrophages and is targeted by human rhinovirus
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Membrane Transduction of Oligoarginine in HeLa Cells Is Not Mediated by Macropinocytosis
Zaro, J. L., Rajapaksa, T. E., Okamoto, C. T., & Shen, W. (2006) · Molecular Pharmaceutics · doi:10.1021/mp0500869 · Cited by 36
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“inhibitor of PI 3-kinase, Wort [48,56,66,67] and its effect on”
BackgroundA ratiometric fluorescent probe for mitochondrial esterase specific detection in living cells
Shen, T., Zang, S., Shu, W., Nie, L., Jing, J., & Zhang, X. (2020) · Dyes and Pigments · doi:10.1016/j.dyepig.2020.108345 · Cited by 33
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Endocytosis-like DNA uptake by cell wall-deficient bacteria
Kapteijn, R., Shitut, S., Aschmann, D., Zhang, L., de Beer, M. A., Daviran, D., Roverts, R., Akiva, A., van Wezel, G. P., Kros, A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33054-w · Cited by 36
Myosin IIB isoform plays an essential role in the formation of two distinct types of macropinosomes
Jiang, J., Kolpak, A., & Bao, Z. (2009) · Cytoskeleton · doi:10.1002/cm.20419 · Cited by 33
“Inhibitors of PI3K inhibit both membrane ruffling and macropinocytosis induced by insulin in epidermoid carcinoma KB cells [Kotani et al., 1995], but only inhibit macropinosome closure not membrane ruffles in EGF-stimulated epidermal A431 cells [Araki et al., 2007].”
BackgroundMethodInfluentialProtein kinase C β and δ isoenzymes mediate cholesterol accumulation in PMA-activated macrophages
Ma, H., Lin, W., Zhao, B., Wu, W., Huang, W., Li, Y., Jones, N. L., & Kruth, H. S. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.08.018 · Cited by 34
Ming‐Lum, A., Shojania, S., So, E., McCarrell, E., Shaw, E., Vu, D., Wang, I., McIntosh, L. P., & Mui, A. L. ‐. (2012) · The FASEB Journal · doi:10.1096/fj.11-201475 · Cited by 34
Molecular imaging analysis of Rab GTPases in the regulation of phagocytosis and macropinocytosis
Egami, Y. (2015) · Anatomical Science International · doi:10.1007/s12565-015-0313-y · Cited by 33
“Phagocytosis via FccRs, the best-characterized pathway of phagocytosis, entails actin polymerization and reorganization, which drive the extension of pseudopods around IgG-opsonized particles to form phagocytic cups (Araki et al. 2003; Swanson 2008; Araki et al. 1996).”
BackgroundCD47 and Nox1 Mediate Dynamic Fluid-Phase Macropinocytosis of Native LDL
Csányi, G., Feck, D. M., Ghoshal, P., Singla, B., Lin, H., Nagarajan, S., Meijles, D. N., Ghouleh, I. A., Cantú‐Medellín, N., Kelley, E. E., et al. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2016.6834 · Cited by 33
“It is logical then that previous reports went on to show that pharmacological inhibitors of PI3K, such as LY294002, inhibit cup closure and macropinosome formation in macrophages (4).”
BackgroundInfluentialPI3Kβ is selectively required for growth factor-stimulated macropinocytosis
Salloum, G., Jakubik, C. T., Erami, Z., Heitz, S. D., Bresnick, A. R., & Backer, J. (2019) · Journal of Cell Science · doi:10.1242/jcs.231639 · Cited by 32
Brodwolf, R., Volz, P., Stellmacher, J., Wolff, C., Unbehauen, M. L., Haag, R., Schäfer‐Korting, M., Zoschke, C., & Alexiev, U. (2020) · Theranostics · doi:10.7150/thno.42581 · Cited by 33
“While almost complete (~90%) inhibition of NC-ICC uptake is observed in the presence of MßCD and genistein as lipid raft/caveolae-mediated uptake inhibitors [63-65], blocking of macropinocytosis via the phosphoinositide 3-kinase inhibitor wortmannin [66] and clathrin-mediated endocytosis by chlorpromazine [67] does no…”
BackgroundErnest James Phillips, T., & Maguire, E. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.652593 · Cited by 33
Rotshenker, S. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.949079 · Cited by 35
Hsieh, C.-H., Nickel, E. A., Chen, J., Schwacha, M. G., Choudhry, M. A., Bland, K. I., & Chaudry, I. H. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803423 · Cited by 33
Rac-Mediated Macropinocytosis Is a Critical Route for Naked Plasmid DNA Transfer in Mice
Fumoto, S., Nishi, J., Ishii, H., Wang, X., Miyamoto, H., Yoshikawa, N., Nakashima, M., Nakamura, J., & Nishida, K. (2009) · Molecular Pharmaceutics · doi:10.1021/mp900042p · Cited by 33
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Macropinocytosis: a pathway to protozoan infection
de Carvalho, T. M. U., Barrias, E., & de Souza, W. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00106 · Cited by 33
“…3-kinases (PI3Ks), which generate PI(3,4,5)P3 from PI(4,5)P2, impair macropinosome formation since the transient and sequential emergence of phosphoinositides PI(3,4,5)P3 and PI(3,4)P2 in the membrane ruffles are essential for macropinocytosis (Araki et al., 1996; Maekawa et al., 2014).”
BackgroundAkt and SGK protein kinases are required for efficient feeding by macropinocytosis
Williams, T. D., Peak‐Chew, S., Paschke, P., & Kay, R. R. (2019) · Journal of Cell Science · doi:10.1242/jcs.224998 · Cited by 30
“PIP3 is vital for efficient macropinocytosis in both amoebae and mammalian cells (Araki et al., 1996; Hoeller et al., 2013; Williams and Kay, 2018b).”
BackgroundTyrosine kinases in neutrophils
Berton, G. (1999) · Current Opinion in Hematology · doi:10.1097/00062752-199901000-00009 · Cited by 33
Determination of cell uptake pathways for tumor inhibitor lysyl oxidase propeptide
Ozdener, G. B., Bais, M. V., & Trackman, P. C. (2015) · Molecular Oncology · doi:10.1016/j.molonc.2015.07.005 · Cited by 33
“Inhibition of PI3K with LY294002 (100 mM) prevents closure of macropinocytotic cups (Araki et al., 1996).”
BackgroundEssential roles of PIKfyve and PTEN on phagosomal phosphatidylinositol 3‐phosphate dynamics
Hazeki, K., Nigorikawa, K., Takaba, Y., Segawa, T., Nukuda, A., Masuda, A., Ishikawa, Y., Kubota, K., Takasuga, S., & Hazeki, O. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.09.043 · Cited by 28
Juks, C., Lorents, A., Arukuusk, P., Langel, Ü., & Pooga, M. (2016) · The FASEB Journal · doi:10.1096/fj.201600811r · Cited by 32
McLaren, J. E., Michael, D. R., Guschina, I. A., Harwood, J. L., & Ramji, D. P. (2011) · Lipids · doi:10.1007/s11745-011-3598-1 · Cited by 36
“3b, blockade of macropinocytosis using the PI3 K inhibitor LY294002 [36] completely abolished the EPA- and DHA-mediated inhibition of LY uptake, thereby potentially providing direct evidence for the involvement of macropinocytosis during this process.”
BackgroundMethodInfluentialPhosphatidylinositol 3-kinases and their roles in phagosome maturation
Thi, E. P., & Reiner, N. E. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.0212053 · Cited by 31
“Class IA PI3Ks are activated following Fc R clustering [38, 39], and the activity of these PI3Ks is needed for closure of phagosomes containing particles 3 m in diameter [40, 41].”
BackgroundThe cytoplasmic domain of FcγRIIA (CD32) participates in phagolysosome formation
Worth, R. G., Mayo-Bond, L., Kim, M.-K., van de Winkel, J. G. J., Todd, R. F., Petty, H. R., & Schreiber, A. D. (2001) · Blood · doi:10.1182/blood.v98.12.3429 · Cited by 32
Co-stimulation-dependent activation of a JNK-kinase in T lymphocytes
Avraham, A., Jung, S., Samuels, Y., Seger, R., & Ben‐Neriah, Y. (1998) · European Journal of Immunology · doi:10.1002/(sici)1521-4141(199808)28:08 · Cited by 71
Phagocytosis: Phenotypically Simple Yet a Mechanistically Complex Process
Kumar, V. (2020) · International Reviews of Immunology · doi:10.1080/08830185.2020.1732958 · Cited by 31
“The PI3K (Phosphoinositide 3Kinases) generated PI 3,4,5-triphosphate [PtdIns(3,4,5)P(3)] restricts to the phagocytic cup and promotes phagocytosis by closing the phagosome and ca2þ signaling [206,207].”
BackgroundEnhancement of Anticancer Efficacy and Tumor Penetration of Sorafenib by Ionic Liquids
Shi, Y., Zhao, Z., Peng, K., Gao, Y., Wu, D., Kim, J., & Mitragotri, S. (2020) · Advanced Healthcare Materials · doi:10.1002/adhm.202001455 · Cited by 31
Cao, Y., Chen, E., Wang, X., Song, J., Zhang, H., & Chen, X. (2023) · Cancer Cell International · doi:10.1186/s12935-023-02859-0 · Cited by 31
“Wortmannin, LY294002 PI3K Inhibit PI3K signaling pathway Preclinical N/A [100, 111]”
BackgroundFormation and closure of macropinocytic cups in Dictyostelium
Lutton, J. E., Coker, H. L. E., Paschke, P., Munn, C. J., King, J., Bretschneider, T., & Kay, R. R. (2023) · Current Biology · doi:10.1016/j.cub.2023.06.017 · Cited by 34
Macropinocytosis contributes to the macrophage foam cell formation in RAW264.7 cells
Yao, W., Li, K., & Liao, K. (2009) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmp066 · Cited by 30
Dubielecka, P. M., Machida, K., Xiong, X., Hossain, S., Ogiue-Ikeda, M., Carrera, A. C., Mayer, B. J., & Kotula, L. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.06.029 · Cited by 30
Interleukin 10 promotes macrophage uptake of HDL and LDL by stimulating fluid-phase endocytosis
Lucero, D., Islam, P., Freeman, L. A., Jin, X., Pryor, M., Tang, J., Kruth, H. S., & Remaley, A. T. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2019.158537 · Cited by 32
“Amiloride, latrunculin A, FITC-dextran (70 KDa), LY and LY294002 were purchased from Sigma-Aldrich (Sigma-Aldrich, St. Louis, MO).”
BackgroundInfluentialExcitotoxicity‐related endocytosis in cortical neurons
Vaslin, A., Puyal, J., Borsello, T., & Clarke, R. C. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04564.x · Cited by 30
“Dextrans greater than about 10 kDa are taken up predominately by macropinocytosis, and 150 kDa dextran is specific for macropinocytosis (Araki et al. 1996).”
BackgroundRossi, A., & Lord, J. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069108 · Cited by 30
“For example, PI3K has also been shown to be indispensable for the correct closure of phagosomes [47].”
BackgroundMeza, I., & Clarke, M. (2004) · Cell Motility and the Cytoskeleton · doi:10.1002/cm.20038 · Cited by 30
Moeenrezakhanlou, A., Shephard, L., Lam, L. L. C., & Reiner, N. E. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.1207833 · Cited by 30
“Phosphatidylinositide 3-kinase (PI3K) through the production of 3 -phosphoinositides has been shown to regulate numerous monocyte/macrophage activities, including cytokine production downstream of Toll-like receptors (TLRs) [2–4], phagocytosis [5], and activation of the phagocyte oxidase [6], among other properties.”
BackgroundRío, D. A. F. D., Soto‐Cruz, I., Garay-Canales, C. A., Ambriz-Peña, X., Soldevila, G., Carretero-Ortega, J., Vázquez‐Prado, J., & Ortega, E. (2011) · Cytokine · doi:10.1016/j.cyto.2011.11.008 · Cited by 30
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Shao, L., Zhao, J., & Zhang, H. (2016) · Journal of General Virology · doi:10.1099/jgv.0.000595 · Cited by 29
“Araki et al. (1996) reported that Wort and LY294002 could block macropinocytic cups closure but not ruffle closure.”
BackgroundKordon, A. O., Abdelhamed, H., Ahmed, H. A., Park, J. Y., Karsi, A., & Pinchuk, L. M. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.02638 · Cited by 28
“Phagocytosis is a receptor-mediated process, and these receptors are classified into two groups: non-opsonic receptors (e.g., Dectin-1 and CD36) and opsonic receptors (e.g., FcγRIIA and Mac-1) (Araki et al., 1996; Schlam et al., 2015; Levin et al., 2016).”
BackgroundWang, Y., Hu, W. S., Ding, B., Chen, D., & Cheng, L. (2020) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2020.111195 · Cited by 29
Veithen, A., Amyere, M., Smissen, P. V. D., Cupers, P., & Courtoy, P. J. (1998) · Journal of Cell Science · doi:10.1242/jcs.111.16.2329 · Cited by 29
Proteomics reveals time-dependent protein corona changes in the intracellular pathway
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Fc Receptors in Antimicrobial Protection
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Cytosolic protein delivery using pH-responsive, charge-reversible lipid nanoparticles
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Rap1 Activation Is Required for Fcγ Receptor-Dependent Phagocytosis
Chung, J., Serezani, C. H., Huang, S. K., Stern, J. N. H., Keskin, D. B., JAGIRDAR, R. M., Brock, T. G., Aronoff, D. M., & Peters-Golden, M. L. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.8.5501 · Cited by 28
“SRBCs were opsonized with a subagglutinating concentration of polyclonal rabbit anti-SRBC IgG as previously described (10).”
Lipid Microdomain‐Dependent Macropinocytosis Determines Compartmentation of Afipia felis
Schneider, B. E., Schueller, C., Utermöhlen, O., & Haas, A. (2006) · Traffic · doi:10.1111/j.1600-0854.2006.00525.x · Cited by 28
“Our above interpretations were based on previous reports that amiloride can indeed inhibit macropinocytosis (45) and that 70 000 MW DTxR is a specific probe for macropinocytosis (19).”
BackgroundRegulation of phagocytosis by TAM receptors and their ligands
Lu, Q., Li, Q., & Lu, Q. (2010) · Frontiers in Biology · doi:10.1007/s11515-010-0034-5 · Cited by 33
“PI3K is a prone signaling pathway to regulate phagocytosis (Araki et al., 1996; Hall et al., 2003; Shankar et al., 2003, 2006; Keating et al., 2006; Kamen et al., 2007; Zheng et al., 2009).”
BackgroundEndocytosis and the internalization of pathogenic organisms: focus on phosphoinositides
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The Tyrosine Kinase Pyk2 Contributes to Complement-Mediated Phagocytosis in Murine Macrophages
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Role of phosphatidylinositol-4,5-bisphosphate 3-kinase signaling in vesicular trafficking
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Ikeda, Y., Kawai, K., Ikawa, A., Kawamoto, K., Egami, Y., & Araki, N. (2017) · Journal of Cell Science · doi:10.1242/jcs.201749 · Cited by 31
“, 2003), whereas the cup closure is PI3K dependent (Araki et al., 1996).”
BackgroundSelf-citationTol, M. J., van der Lienden, M. J. C., Gabriel, T. L., Hagen, J. J., Scheij, S., Veenendaal, T., Klumperman, J., Donker-Koopman, W. E., Verhoeven, A. J., Overkleeft, H., et al. (2018) · Autophagy · doi:10.1080/15548627.2017.1419118 · Cited by 27
“of the class III phosphatidylinositol 3-kinase (PtdIns3K) and fluid-phase endocytosis [41] (confirmed by monitoring the”
BackgroundGrønlien, H. K., Berg, T., & Løvlie, A. (2002) · Journal of Experimental Biology · doi:10.1242/jeb.205.14.2089 · Cited by 27
Intracellular pathogens in membrane interactions and vacuole biogenesis
Gorvel, J. (2004) · Cited by 27
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“For example, macrophages treated with the phosphatidylinositol 3-kinase inhibitor wortmannin or LY294002 (3, 35) exhibit defects in completion of FcRgamma-triggered phagocytosis manifested as failure of fusion of the pseudopod tips.”
BackgroundPKCδ stimulates macropinocytosis via activation of SSH1-cofilin pathway
Singla, B., Lin, H., Ghoshal, P., Cherian‐Shaw, M., & Csányi, G. (2018) · Cellular Signalling · doi:10.1016/j.cellsig.2018.09.018 · Cited by 26
“M-CSF is a widely used stimulator of macropinocytosis in macrophages (10, 21, 48, 49).”
BackgroundChen, G., Su, Y., Hsu, C., Lo, Y., Huang, S., Ke, J.-H., Kuo, Y., & Wang, L. (2014) · Journal of Materials Chemistry B · doi:10.1039/c4tb00543k · Cited by 26
Francisella Subverts Innate Immune Signaling: Focus On PI3K/Akt
Cremer, T. J., Butchar, J. P., & Tridandapani, S. (2011) · Frontiers in Microbiology · doi:10.3389/fmicb.2011.00013 · Cited by 27
“…regulates host responses PI3K signaling is known to regulate numerous cellular processes such as autophagy (Petiot et al., 2000), phagocytosis (Araki et al., 1996), cell survival, oxidative burst (Chen et al., 2003; Hoyal et al., 2003), and inflammatory cytokine production (Parsa et al.,…”
Extracellular IgC2 Constant Domains of CEACAMs Mediate PI3K Sensitivity during Uptake of Pathogens
Voges, M., Bachmann, V. A., Naujoks, J., Kopp, K., & Hauck, C. R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0039908 · Cited by 25
“Recently, we made the surprising observation that phosphatidylinositol-39 kinase (PI3Ks) activity is not involved in CEACAM3-triggered phagocytosis by human granulocytes [31], despite the well-characterized role of phosphatidylinositol phosphates (PIPs) in numerous endocytic processes [32,33].”
BackgroundSpatiotemporal Localization of Rab20 in Live RAW264 Macrophages during Macropinocytosis
Egami, Y., & Araki, N. (2012) · ACTA HISTOCHEMICA ET CYTOCHEMICA · doi:10.1267/ahc.12014 · Cited by 26
“2–5 μm), by fission from the plasma membrane [3, 33].”
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“26 To elucidate the detailed mechanism of macropinocytosis-dependent CNP internalizations, non-IPF and IPF fibroblasts (n = 6/group) were pretreated with three different chemical inhibitors for the inhibition of early, middle, and late phases of macropinocytosis, respectively.”
Zaru, R., Mollahan, P., & Watts, C. K. W. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m708069200 · Cited by 26
Albrecht, I., Gatfield, J., Mini, T., Jenö, P., & Pieters, J. (2006) · International Immunology · doi:10.1093/intimm/dxl013 · Cited by 25
“Both induced and constitutive macropinosome formations are dependent on the activity of phosphatidylinositol (PI)-3-kinase ( 38 , 42) and the activity of Rho family member Rac 1 (43, 44).”
BackgroundMolecular Mechanisms of Host–Pathogen Interaction: Entry and Survival of Mycobacteria in Macrophages
Gatfield, J., & Pieters, J. (2003) · Advances in immunology · doi:10.1016/s0065-2776(03)81002-7 · Cited by 25
Nakayama, Y., Nakamura, N., Oki, S., Wakabayashi, M., Ishihama, Y., Miyake, A., Itoh, N., & Kurosaka, A. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.370932 · Cited by 25
“DextranMr 3,000 (small) is a marker for all types of pinocytosis, such as receptor-mediated endocytosis and macropinocytosis, andMr 10,000 dextran (large) is endocytosed primarily through macropinocytosis (26, 27).”
BackgroundStack, T., Vahabikashi, A., Johnson, M., & Scott, E. A. (2018) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.36376 · Cited by 26
“Dextran can enter macrophages through receptor mediated endocytosis, macropinocytosis and micropinocytosis.(30,31) These dyes are pH sensitive and increase their fluorescence intensity with increasing acidity, meaning that they should increase in intensity as they move through the endocytic pathway into the lysosome.”
Self-citation
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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