PI 3-kinase independent role for AKT in F-actin regulation during outer segment phagocytosis by RPE cells
Open accessAbstract
Daily phagocytosis of photoreceptor outer segment fragments (POS) by the retinal pigment epithelium (RPE) is essential for vision. RPE cells use an uptake machinery that is highly similar to the one macrophages use to phagocytose apoptotic cells. In both forms of phagocytosis, particle binding induces phagocyte signaling that is required for F-actin assembly and re-arrangement beneath bound particles. Macrophage binding of apoptotic cells stimulates PI3 kinases (PI3K) and AKT kinases (AKT), which may be downstream of PI3K, and PI3K inhibition decreases engulfment. Here, we used specific inhibitory agents to investigate whether and how PI3K and AKT contribute to RPE phagocytosis. Either PI3K or AKT inhibition eliminated AKT activation by RPE cells in response to POS and increased the numbers of POS bound by RPE cells. Analyzing the quality of bound POS, we found a higher fraction of POS associated with F-actin phagocytic cups and myosin II in RPE receiving AKT inhibitor. In these cells, individual POS also recruited more F-actin and myosin II than POS in control cells. In contrast, PI3K inhibition did not alter frequency of phagocytic cups but individual cups contained less F-actin (but similar levels of myosin II) compared to control cups. Annexin AII, another phagocytic cup protein of RPE cells, associated with bound POS regardless of inhibitor treatment. POS engulfment proceeded normally if cells already carried surface-bound POS when receiving inhibitors. However, PI3K inhibition during POS binding blocked subsequent POS engulfment. In striking contrast, AKT inhibition had no effect on POS engulfment. Taken together, these results suggest distinct regulatory roles of PI3K and AKT during POS phagocytosis by RPE cells.
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PI3K is required for OS engulfment, possibly due to a role in promoting phagocytic cup formation, while AKT is not required for ingestion and appears to restrict the size of the phagocytic cups and myosin-2 recruitment to the cup.
“PI3K is required for OS engulfment, possibly due to a role in promoting phagocytic cup formation, while AKT is not required for ingestion, and appears to restrict the size of the phagocytic cups and myosin-2 recruitment to the cup (Bulloj et al., 2013).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Bulloj et al., 2013
Despite being a downstream effector of PI3K, AKT functions independently from PI3K during phagocytosis.
“Moreover, despite being a downstream effector of PI3K, AKT functions independently from PI3K during phagocytosis (Bulloj et al., 2013).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Bulloj et al., 2013
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Cites
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216 · see citing works
Vlahos, C. J., Matter, W. F., Hui, K. Y., & Brown, R. F. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37680-9 · Cited by 3,248 · see citing works
Mechanisms of phagocytosis in macrophages
Aderem, A., & Underhill, D. M. (1999) · Annual Review of Immunology · doi:10.1146/annurev.immunol.17.1.593 · Cited by 2,854 · see citing works
Jacinto, E., Facchinetti, V., Liu, D., Soto, N., Wei, S., Jung, S. Y., Huang, Q., Qin, J., & Su, B. (2006) · Cell · doi:10.1016/j.cell.2006.08.033 · Cited by 1,407 · see citing works
Araki, N., Johnson, M. T., & Swanson, J. A. (1996) · The Journal of cell biology · doi:10.1083/jcb.135.5.1249 · Cited by 949 · see citing works
Phagocytosis and the actin cytoskeleton
May, R. C., & Machesky, L. M. (2001) · Journal of Cell Science · doi:10.1242/jcs.114.6.1061 · Cited by 715 · see citing works
Gal, A., Li, Y., Thompson, D. A., Weir, J., Orth, U., Jacobson, S. G., Apfelstedt-Sylla, E., & Vollrath, D. (2000) · Nature Genetics · doi:10.1038/81555 · Cited by 679 · see citing works
Vieira, O. V., Botelho, R. J., Rameh, L. E., Brachmann, S. M., Matsuo, T., Davidson, H. W., Schreiber, A. D., Backer, J., Cantley, L. C., & Grinstein, S. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.200107069 · Cited by 530 · see citing works
Regulation of Protein Kinase B/Akt-Serine 473 Phosphorylation by Integrin-linked Kinase
Persad, S., Attwell, S., Gray, V., Mawji, N. M., Deng, J. T., Leung, D., Yan, J., Sanghera, J. S., Walsh, M. P., & Dedhar, S. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102940200 · Cited by 497 · see citing works
Balendran, A., Casamayor, A., Deák, M., Paterson, A., Gaffney, P. R. J., Currie, R. A., Downes, C. P., & Alessi, D. R. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80186-9 · Cited by 429 · see citing works
A requirement for phosphatidylinositol 3-kinase in pseudopod extension
Cox, D., Tseng, C.-C., Bjekic, G., & Greenberg, S. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.3.1240 · Cited by 410 · see citing works
The bisretinoids of retinal pigment epithelium
Sparrow, J. R., Gregory-Roberts, E., Yamamoto, K., Blonska, A., Ghosh, S. K., Ueda, K., & Zhou, J. (2012) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2011.12.001 · Cited by 392 · see citing works
Finnemann, S. C., Bonilha, V. L., Marmorstein, A. D., & Rodriguez-Boulan, E. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.24.12932 · Cited by 382 · see citing works
Self-citationNeutrophil clearance: when the party is over, clean-up begins
Bratton, D. L., & Henson, P. M. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.04.009 · Cited by 350 · see citing works
Loss of synchronized retinal phagocytosis and age-related blindness in mice lacking αvβ5 integrin
Nandrot, E. F., Kim, Y., Brodie, S. E., Huang, X., Sheppard, D., & Finnemann, S. C. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20041447 · Cited by 319 · see citing works
Self-citationFinnemann, S. C., Leung, L. W., & Rodriguez-Boulan, E. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.052025899 · Cited by 283 · see citing works
A 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 · see citing works
Marshall, 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 · see citing works
Phosphoinositide 3-kinase activates Rac by entering in a complex with Eps8, Abi1, and Sos-1
Innocenti, M., Frittoli, E., Ponzanelli, I., Falck, J. R., Brachmann, S. M., Fiore, P. P. D., & Scita, G. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200206079 · Cited by 264 · see citing works
Roles of PI3Ks in leukocyte chemotaxis and phagocytosis
Stephens, L., Ellson, C. D., & Hawkins, P. T. (2002) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(02)00311-3 · Cited by 258 · see citing works
Feng, W., Yasumura, D., Matthes, M. T., LaVail, M. M., & Vollrath, D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m107876200 · Cited by 244 · see citing works
Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis
Nandrot, E. F., Anand, M., Almeida, D., Atabai, K., Sheppard, D., & Finnemann, S. C. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0704756104 · Cited by 241 · see citing works
Self-citationPI3K‐independent AKT activation in cancers: A treasure trove for novel therapeutics
Mahajan, K. N., & Mahajan, N. P. (2012) · Journal of Cellular Physiology · doi:10.1002/jcp.24065 · Cited by 229 · see citing works
Involvement 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 · see citing works
Focal adhesion kinase signaling promotes phagocytosis of integrin‐bound photoreceptors
Finnemann, S. C. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg416 · Cited by 208 · see citing works
Self-citationRegulation of actin dynamics by annexin 2
Hayes, M., Shao, D., Bailly, M., & Moss, S. E. (2006) · EMBO Journal · doi:10.1038/sj.emboj.7601078 · Cited by 205 · see citing works
Rac signaling in breast cancer: A tale of GEFs and GAPs
Wertheimer, E. V., Gutiérrez-Uzquiza, Á., Rosemblit, C., López‐Haber, C., Sosa, M. S., & Kazanietz, M. G. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.08.011 · Cited by 204 · see citing works
Hu, Y., Qiao, L., Wang, S., et al. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm000117y · Cited by 195 · see citing works
Distribution of actin-binding protein and myosin in macrophages during spreading and phagocytosis.
Stendahl, O. I., Hartwig, J. H., Brotschi, E. A., & Stossel, T. P. (1980) · The Journal of Cell Biology · doi:10.1083/jcb.84.2.215 · Cited by 168 · see citing works
Ruggiero, L., Connor, M. P., Chen, J., Langen, R., & Finnemann, S. C. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1121101109 · Cited by 156 · see citing works
Dynamics of Cytoskeletal Proteins during Fcγ Receptor-mediated Phagocytosis in Macrophages
Diakonova, M., Bokoch, G., & Swanson, J. A. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.01-05-0273 · Cited by 151 · see citing works
Macrophage and Retinal Pigment Epithelium Phagocytosis
Finnemann, S. C., & Rodriguez-Boulan, E. J. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.190.6.861 · Cited by 144 · see citing works
Self-citationRat retinal pigment epithelial cells show specificity of phagocytosis in vitro.
Mayerson, P. L., & Hall, M. O. (1986) · The Journal of Cell Biology · doi:10.1083/jcb.103.1.299 · Cited by 130 · see citing works
Beemiller, P., Hoppe, A. D., & Swanson, J. A. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040162 · Cited by 121 · see citing works
Reddy, S. M., Hsiao, K.-C., Abernethy, V. E., Fan, H., Longacre, A., Lieberthal, W., Rauch, J., Koh, J. S., & Levine, J. S. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.2.702 · Cited by 110 · see citing works
Nho, R. S., Hong, X., Kahm, J., Kleidon, J., Diebold, D., & Henke, C. A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m411798200 · Cited by 100 · see citing works
Identification of N10-Substituted Phenoxazines as Potent and Specific Inhibitors of Akt Signaling
Thimmaiah, K. N., Easton, J. B., Germain, G. S., Morton, C. L., Kamath, S., Buolamwini, J. K., & Houghton, P. J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507057200 · Cited by 99 · see citing works
Leverrier, Y., Okkenhaug, K., Sawyer, C., Bilancio, A., Vanhaesebroeck, B., & Ridley, A. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m306649200 · Cited by 90 · see citing works
Mertk drives myosin II redistribution during retinal pigment epithelial phagocytosis
Strick, D. J., Feng, W., & Vollrath, D. (2009) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.08-3058 · Cited by 81 · see citing works
Mao, Y., & Finnemann, S. C. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-10-0840 · Cited by 80 · see citing works
Self-citationDifferential Association of Phosphatidylinositol 3-Kinase, SHIP-1, and PTEN with Forming Phagosomes
Kamen, L. A., Levinsohn, J. L., & Swanson, J. A. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-01-0061 · Cited by 79 · see citing works
Annexin A2 regulates phagocytosis of photoreceptor outer segments in the mouse retina
Law, A.-L., Ling, Q., Hajjar, K. A., Futter, C. E., Greenwood, J., Adamson, P., Wavre-Shapton, S. T., Moss, S. E., & Hayes, M. J. (2009) · Molecular Biology of the Cell · doi:10.1091/mbc.e08-12-1204 · Cited by 75 · see citing works
Chaitin, M. H., & Hall, M. O. (1983) · PubMed · Cited by 58 · see citing works
Nandrot, E. F., Silva, K. E., Scelfo, C., & Finnemann, S. C. (2012) · Biology of the Cell · doi:10.1111/boc.201100076 · Cited by 52 · see citing works
Self-citationAllen, L. H., Allgood, J. A., Han, X., & Wittine, L. M. (2005) · Journal of Leukocyte Biology · doi:10.1189/jlb.0205091 · Cited by 47 · see citing works
Phagocytosis of Wild-TypeLegionella pneumophilaOccurs through a Wortmannin-Insensitive Pathway
Khelef, N., Shuman, H. A., & Maxfield, F. R. (2001) · Infection and Immunity · doi:10.1128/iai.69.8.5157-5161.2001 · Cited by 46 · see citing works
MERTK interactions with SH2-domain proteins in the retinal pigment epithelium
Shelby, S. J., Colwill, K., Dhe-Paganon, S., Pawson, T., & Thompson, D. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0053964 · Cited by 35 · see citing works
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The cell biology of the retinal pigment epithelium
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Lewis, T. R., Kundinger, S. R., Link, B. A., Insinna, C., & Besharse, J. C. (2018) · BMC Cell Biology · doi:10.1186/s12860-018-0177-9 · Cited by 35 · see citing works
- Authors
- Bulloj, A., Duan, W., & Finnemann, S. C.
- Affiliations
- Fordham University (US)
- Corresponding author
- Finnemann, Silvia C.
- ORCID
- Finnemann, Silvia C.
- Venue
- Experimental Eye Research
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 113
- Pages
- 9-18
- ISSN
- 0014-4835 (ISSN-L)
- PMC
- PMC3737417
- OpenAlex
- W1992994305
- Cited by
- 39
- References
- 47
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 7 · 2019: 3 · 2018: 2 · 2017: 6 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 2
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Experimental Eye Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- photoreceptor outer segment phagocytosis, retinal pigment epithelium, PI3-kinase, Akt, F-actin assembly, myosin II, phagocytic cup, engulfment, phagocytosis of apoptotic cells, PI3K-independent signaling
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Actins, Animals, Cell Membrane, Cells, Cultured, Chromones, Electrophoresis, Polyacrylamide Gel, Enzyme Inhibitors, Actin Cytoskeleton, Morpholines, Phagocytosis, Swine, Immunoblotting, Signal Transduction, Fluorescent Antibody Technique, Indirect, Proto-Oncogene Proteins c-akt, Rats, Retinal Pigment Epithelium, Retinal Photoreceptor Cell Outer Segment, Phosphatidylinositol 3-Kinase
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