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Cited by 506Phagocytosis and Immune RegulationMonoclonal and Polyclonal Antibodies ResearchImmune Response and Inflammation

A critical role for Syk in signal transduction and phagocytosis mediated by Fcγ receptors on macrophages

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Crowley, Mary T., Costello, Patrick S., Fitzer-Attas, Cheryl J., Turner, Martin, Meng, Fanying, Lowell, Clifford, Tybulewicz, Victor L. J., DeFranco, Anthony L.·1997·The Journal of Experimental Medicine
DOI 10.1084/jem.186.7.1027PMC PMC2199061
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Abstract

Receptors on macrophages for the Fc region of IgG (FcγR) mediate a number of responses important for host immunity. Signaling events necessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after FcγR cross-linking. Macrophages derived from Syk-deficient (Syk−) mice were defective in phagocytosis of particles bound by FcγRs, as well as in many FcγR-induced signaling events, including tyrosine phosphorylation of a number of cellular substrates and activation of MAP kinases. In contrast, Syk− macrophages exhibited normal responses to another potent macrophage stimulus, lipopolysaccharide. Phagocytosis of latex beads and Escherichia coli bacteria was also not affected. Syk− macrophages exhibited formation of polymerized actin structures opposing particles bound to the cells by FcγRs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked FcγR-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for FcγR-mediated phagocytosis. Macrophages derived from mice deficient for the three members of the Src-family of kinases expressed in these cells, Hck, Fgr, and Lyn, exhibited poor Syk activation upon FcγR engagement, accompanied by a delay in FcγR-mediated phagocytosis. These observations demonstrate that Syk is critical for FcγR-mediated phagocytosis, as well as for signal transduction in macrophages. Additionally, our findings provide evidence to support a model of sequential tyrosine kinase activation by FcγR's analogous to models of signaling by the B and T cell antigen receptors.

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  • Recruitment and activation of Syk is critical for FcγR-mediated phagocytosis, as shown by the inability of Syk−/− macrophages to internalize IgG-opsonized particles.

    “Recruitment and activation of this tyrosine kinase is critical for FcγR-mediated phagocytosis, as demonstrated by the inability of macrophages from Syk−/− mice to internalize IgG-opsonized particles (Crowley et al. 1997; Kiefer et al. 1998).”

    From Localized Biphasic Changes in Phosphatidylinositol-4,5-Bisphosphate at Sites of Phagocytosis (2000) · cites this paper as Crowley et al. 1997

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  1. [1]Ravetch JV Kinet JP Fc receptors Ann Rev Immunol 1991 9 457 492 1910686
  2. [2]Brooks D Ravetch JV Fc receptor signaling Adv Exp Med Biol 1994 365 185 195 7887303
  3. [3]Takai T Li M Sylvestre D Clynes R Ravetch JV FcR gamma chain deletion results in pleiotrophic effector cell defects Cell 1994 76 519 529 8313472
  4. [4]Takai T Ono M Hikida M Ohmori H Ravetch JV Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice Nature (Lond) 1996 379 346 349 8552190
  5. [5]Ravetch JV Fc receptors: rubor redux Cell 1994 78 553 560 8069908
  6. [6]Stockinger B Capacity of antigen uptake by B cells, fibroblasts or macrophages determines efficiency of presentation of a soluble self antigen (C5) to T lymphocytes Eur J Immunol 1992 22 1271 1278 1577067
  7. [7]Greenberg S Chang P Silverstein S Tyrosine phosphorylation is required for Fc receptor-mediated phagocytosis in mouse macrophages J Exp Med 1993 177 529 534 7678851 PMC2190886
  8. [8]Indik ZK Park J Hunter S Schreiber A The molecular dissection of Fcγ receptor mediated phagocytosis Blood 1995 86 4389 4399 8541526
  9. [9]Hutchinson MJ Harrison PT Floto RA Allen JM Fc gamma receptor-mediated phagocytosis requires tyrosine kinase activity and is ligand independent Eur J Immunol 1995 25 481 487 7875211
  10. [10]Kiener PA Rankin BM Burkhardt AL Schieven GL Gilliland LK Rowley R Bolen JB Ledbetter JA Cross-linking of Fc gamma receptor I (Fc gamma RI) and receptor II (Fc gamma RII) on monocytic cells activates a signal transduction pathway common to both Fc receptors that involves the stimulation of p72 Syk protein tyrosine kinase J Biol Chem 1993 268 24442 24448 8226994
  11. [11]Durden DL Liu YB Protein-tyrosine kinase p72syk in Fc gamma RI receptor signaling Blood 1994 84 2102 2108 7522622
  12. [12]Darby C Geahlen RL Schreiber AD Stimulation of macrophage Fc gamma RIIIA activates the receptor-associated protein tyrosine kinase Syk and induces phosphorylation of multiple proteins including p95Vav and p62/GAP-associated protein J Immunol 1994 152 5429 5437 8189062
  13. [13]Greenberg S Chang P Wang D Xavier R Seed B Clustered syk tyrosine kinase domains trigger phagocytosis Proc Natl Acad Sci USA 1996 93 1103 1107 8577722 PMC40038
  14. [14]Gold MR Law DA DeFranco AL Stimulation of protein tyrosine phosphorylation by the B-lymphocyte antigen receptor Nature (Lond) 1990 345 810 813 1694265
  15. [15]Richards JD Gold MR Hourihane SL DeFranco AL Matsuuchi L Reconstitution of B cell antigen receptor-induced signaling events in a nonlymphoid cell line by expressing the Syk protein-tyrosine kinase J Biol Chem 1996 271 6458 6466 8626447
  16. [16]Hambleton J Weinstein SL Lem L DeFranco AL Activation of c-Jun N-terminal kinase in bacterial lipopolysaccharide-stimulated macrophages Proc Natl Acad Sci USA 1996 93 2774 2778 8610116 PMC39708
  17. [17]Turner M Mee PJ Costello PS Williams O Price AA Duddy LP Furlong MT Geahlen RL Tybulewicz VL Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk Nature (Lond) 1995 378 298 302 7477352
  18. [18]Meng F Lowell CA Lipopolysaccharide (LPS)- induced macrophage activation and signal transduction in the absence of Src-family kinases Hck, Fgr, and Lyn J Exp Med 1997 185 1661 1670 9151903 PMC2196288
  19. [19]Crowley MT Harmer SL DeFranco AL Activation-induced association of a 145-kDa tyrosine-phosphorylated protein with shc and syk in B lymphocytes and macrophages J Biol Chem 1996 271 1145 1152 8557643
  20. [20]DeFranco AL Transmembrane signaling by antigen receptors of B and T lymphocytes Curr Biol 1995 7 163 175 7612267
  21. [21]van Oers NS Killeen N Weiss A Lck regulates the tyrosine phosphorylation of the T cell receptor subunits and ZAP-70 in murine thymocytes J Exp Med 1996 183 1053 1062 8642247 PMC2192313
  22. [22]Bewarder N Weinrich V Budde P Hartmann D Flaswinkel H Reth M Frey J In vivo and in vitro specificity of protein tyrosine kinases for immunoglobulin G receptor (Fc gamma RII) phosphorylation Mol Cell Biol 1996 16 4735 4743 8756631 PMC231474
  23. [23]Johnson SA Pleiman CM Pao L Schneringer J Hippen K Cambier JC Phosphorylated immunoreceptor signaling motifs (ITAMs) exhibit unique abilities to bind and activate Lyn and Syk tyrosine kinases J Immunol 1995 155 4596 4603 7594458
  24. [24]Bernhard W Gbarah A Sharon N Lectinophagocytosis of type 1 fimbriated (mannose-specific) Escherichia coliin the mouse peritoneum J Leukocyte Biol 1992 52 343 348 1355788
  25. [25]Yamaya M Fukushima T Sekizawa K Ohrui T Sasaki H Cytoplasmic motility reflects phagocytic activity in alveolar macrophages from dog lungs Respir Physiol 1995 101 199 205 8570922
  26. [26]Tuijnman WB Capel PJ van de Winkel JG Human low-affinity IgG receptor Fc gamma RIIa (CD32) introduced into mouse fibroblasts mediates phagocytosis of sensitized erythrocytes Blood 1992 79 1651 1656 1532752
  27. [27]Geng Y Gulbins E Altman A Lotz M Monocyte deactivation by interleukin 10 via inhibition of tyrosine kinase activity and the Ras signaling pathway Proc Natl Acad Sci USA 1994 91 8602 8606 8078929 PMC44654
  28. [28]Ninomiya N Hazeki K Fukui Y Seya T Okada T Hazeki O Ui M Involvement of phosphatidylinositol 3-kinase in Fc gamma receptor signaling J Biol Chem 1994 269 22732 22737 7521331
  29. [30]Suzuki T Signal transduction mechanisms through Fc gamma receptors on the mouse macrophage surface FASEB J 1991 5 187 193 1706281
  30. [33]Shapira L Takashiba S Champagne C Amar S Van Dyke TE Involvement of protein kinase C and protein tyrosine kinase in lipopolysaccharide-induced TNF- alpha and IL-1 beta production by human monocytes J Immunol 1994 153 1818 1824 7519214
  31. [34]Chanmugam P Feng L Liou S Jang BC Boudreau M Yu G Lee JH Kwon HJ Beppu T Yoshida M Radicicol, a protein tyrosine kinase inhibitor, suppresses the expression of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide and in experimental glomerulonephritis J Biol Chem 1995 270 5418 5426 7890656
  32. [35]Downward J The GRB2/Sem-5 adaptor protein FEBS Lett 1994 338 113 117 8307166
  33. [36]Costello PST Walters M Cunningham AE Bauer CN Downward PH Tybulewicz VLJ Critical role for the tyrosine kinase Syk in signalling through the high affinity IgE receptor of mast cells Oncogene 1996 13 2595 2605 9000133
  34. [37]Gelfand EW Weinberg K Mazer BD Kadlecek TA Weiss A Absence of ZAP-70 prevents signaling through the antigen receptor on peripheral blood T cells but not on thymocytes J Exp Med 1995 182 1057 1065 7561679 PMC2192291
  35. [38]Roifman CM A mutation in zap-70 protein tyrosine kinase results in a selective immunodeficiency J Clin Immunol 1995 15 52 62 8613493
  36. [39]Takata M Sabe H Hata A Inazu T Homma Y Nukada T Yamamura H Kurosaki T Tyrosine kinases Lyn and Syk regulate B cell receptor-coupled Ca2+mobilization through distinct pathways EMBO J 1994 13 1341 1349 8137818 PMC394950
  37. [40]Keegan AD Paul WE Multichain immune recognition receptors: similarities in structure and signaling pathways Immunol Today 1992 13 63 68 1575894
  38. [41]Osman N Turner H Lucas S Reif K Cantrell DA The protein interactions of the immunoglobulin receptor family tyrosine-based activation motifs present in the T cell receptor zeta subunits and the CD3 gamma, delta and epsilon chains Eur J Immunol 1996 26 1063 1068 8647168
  39. [42]Chacko GW Brandt JT Coggeshall KM Anderson CL Phosphoinositide 3-kinase and p72syk noncovalently associate with the low affinity Fc gamma receptor on human platelets through an immunoreceptor tyrosine-based activation motif. Reconstitution with synthetic phosphopeptides J Biol Chem 1996 271 10775 10781 8631888
  40. [43]Allen LH Aderem A Molecular definition of distinct cytoskeletal structures involved in complement- and Fc receptor-mediated phagocytosis in macrophages J Exp Med 1996 184 627 637 8760816 PMC2192718
  41. [44]Lennartz MR Brown EJ Arachidonic acid is essential for IgG Fc receptor-mediated phagocytosis by human monocytes J Immunol 1991 147 621 626 1830070
  42. [45]Damen JE Liu L Rosten P Humphries RK Jefferson AB Majerus PW Krystal G The 145-kDa protein induced to associate with Shc by multiple cytokines is an inositol tetraphosphate and phosphatidylinositol 3,4,5-triphosphate 5-phosphatase Proc Natl Acad Sci USA 1996 93 1689 1693 8643691 PMC40003
  43. [47]Nobes CD Hall A Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia Cell 1995 81 53 62 7536630
  44. [48]Hawkins PT Eguinoa A Qiu RG Stokoe D Cooke FT Walters R Wennstrom S Claesson-Welsh L Evans T Symons M PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase Curr Biol 1995 5 393 403 7627555
  45. [49]Stephens L Hawkins PT Eguinoa A Cooke F A heterotrimeric GTPase-regulated isoform of PI3K and the regulation of its potential effectors Philos Trans R Soc Lond Ser B Biol Sci 1996 351 211 215 8650268

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Authors
Crowley, M. T., Costello, P. S., Fitzer-Attas, C. J., Turner, M., Meng, F., Lowell, C., Tybulewicz, V. L. J., & DeFranco, A. L.
Affiliations
  • University of California, San Francisco (US)
  • From the G.W. Hooper Foundation, *Department of Microbiology and Immunology, and ‡Department of Laboratory Medicine, University of California, San Francisco, California 94143-0552; and the §National Institute for Medical Research, London NW7 1AA, United Kingdom
Corresponding author
Crowley, Mary T.
ORCID
Venue
The Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
1997-10-06
Volume
186
Issue
7
Pages
1027-1039
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.186.7.1027
PMC
PMC2199061
OpenAlex
W1995900983
Cited by
506
References
4
Citations by year
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FWCI
12.12
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
  • Spiral (Imperial College London) (submittedVersion)
Funders
  • National Institutes of Health (5r01ai033442-07)
  • Medical Research Council
  • National Institute of Allergy and Infectious Diseases (T32AI007334, T32 AI 07334, AI33442, AI20038, R37AI020038, R56AI020038, R01AI020038)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
Syk, Fc gamma receptor, macrophages, phagocytosis, signal transduction, Src family kinases, Hck, Fgr, Lyn kinase, tyrosine kinase activation, actin polymerization, phosphatidylinositol 3-kinase, MAPK activation, IgG, lipopolysaccharide, Escherichia coli, latex beads
MeSH terms
Syk Kinase, Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Enzyme Precursors, Erythrocytes, Lipopolysaccharides, Liver, Macrophages, Microspheres, Phagocytosis, Phosphorylation, Protein-Tyrosine Kinases, Signal Transduction, Cytokines, Receptors, IgG, Calcium-Calmodulin-Dependent Protein Kinases, Mice, Knockout, src-Family Kinases, Phosphatidylinositol 3-Kinases, Intracellular Signaling Peptides and Proteins, Mice

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