The DOI matches its Crossref record; 51 of the 51 references it cites were found in a registry or an index.
Tyrosine kinase Btk regulates E-selectin–mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) γ2 and PI3Kγ pathways
Open accessAbstract
Selectins mediate leukocyte rolling, trigger β2-integrin activation, and promote leukocyte recruitment into inflamed tissue. E-selectin binding to P-selectin glycoprotein ligand 1 (PSGL-1) leads to activation of an immunoreceptor tyrosine-based activation motif (ITAM)–dependent pathway, which in turn activates the spleen tyrosine kinase (Syk). However, the signaling pathway linking Syk to integrin activation after E-selectin engagement is unknown. To identify the pathway, we used different gene-deficient mice in autoperfused flow chamber, intravital microscopy, peritonitis, and biochemical studies. We report here that the signaling pathway downstream of Syk divides into a phospholipase C (PLC) γ2– and phosphoinositide 3-kinase (PI3K) γ–dependent pathway. The Tec family kinase Bruton tyrosine kinase (Btk) is required for activating both pathways, generating inositol-3,4,5-trisphosphate (IP3), and inducing E-selectin–mediated slow rolling. Inhibition of this signal-transduction pathway diminished Gαi-independent leukocyte adhesion to and transmigration through endothelial cells in inflamed postcapillary venules of the cremaster. Gαi-independent neutrophil recruitment into the inflamed peritoneal cavity was reduced in Btk−/− and Plcg2−/− mice. Our data demonstrate the functional importance of this newly identified signaling pathway mediated by E-selectin engagement.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“PLCγ2 also has a role in neutrophil recruitment via Btk in regulating E-selectin–mediated integrin activation, which facilitates leukocyte rolling and infiltration into inflamed tissues, and subsequent PI3Kγ pathways (87).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [87]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Getting to the site of inflammation: the leukocyte adhesion cascade updated
Ley, K., Laudanna, C., Cybulsky, M. I., & Nourshargh, S. (2007) · Nature Reviews Immunology · doi:10.1038/nri2156 · Cited by 4,354
Self-citationVetrie, D. L. P., Vořechovský, I., Sideras, P., Holland, J., Davies, A. F., Flinter, F. A., Hammarström, L. L. G., Kinnon, C., Levinsky, R. J., Bobrow, M., et al. (1993) · Nature · doi:10.1038/361226a0 · Cited by 1,465
Katso, R., Okkenhaug, K., Ahmadi, K., White, S., Timms, J. F., & Waterfield, M. D. (2001) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.17.1.615 · Cited by 1,234
Central Role for G Protein-Coupled Phosphoinositide 3-Kinase γ in Inflammation
Hirsch, E., Katanaev, V. L., Garlanda, C., Azzolino, O., Pirola, L., Silengo, L., Sozzani, S., Mantovani, A., Altruda, F., & Wymann, M. P. (2000) · Science · doi:10.1126/science.287.5455.1049 · Cited by 1,209
Self-citationPI3K in lymphocyte development, differentiation and activation
Okkenhaug, K., & Vanhaesebroeck, B. (2003) · Nature reviews. Immunology · doi:10.1038/nri1056 · Cited by 824
Roles of PLC-β2 and -β3 and PI3Kγ in Chemoattractant-Mediated Signal Transduction
Li, Z., Jiang, H., Xie, W., Zhang, Z., Smrcka, A. V., & Wu, D. (2000) · Science · doi:10.1126/science.287.5455.1046 · Cited by 807
The Tail of Integrins, Talin, and Kindlins
Moser, M., Legate, K. R., Zent, R., & Fässler, R. (2009) · Science · doi:10.1126/science.1163865 · Cited by 782
Blockade of PI3Kγ suppresses joint inflammation and damage in mouse models of rheumatoid arthritis
Camps, M., Rückle, T., Ji, H., Ardissone, V., Rintelen, F., Shaw, J. P., Ferrandi, C., Chabert, C., Gilliéron, C., Françon, B., et al. (2005) · Nature Medicine · doi:10.1038/nm1284 · Cited by 753
Self-citationFaust, N., Varas, F., Kelly, L. M., Heck, S., & Graf, T. (2000) · Blood · doi:10.1182/blood.v96.2.719 · Cited by 751
Intracellular signalling controlling integrin activation in lymphocytes
Kinashi, T. (2005) · Nature reviews. Immunology · doi:10.1038/nri1646 · Cited by 555
Syk tyrosine kinase required for mouse viability and B-cell development
Cheng, A. M., Rowley, B., Pao, W., Hayday, A., Bolen, J. B., & Pawson, T. (1995) · Nature · doi:10.1038/378303a0 · Cited by 528
Mohamed, A. J., Yu, L., Bäckesjö, C., Vargas, L., Faryal, R., Aints, A., Christensson, B., Berglöf, A., Vihinen, M., Nore, B. F., et al. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00741.x · Cited by 516
Phospholipase Cγ2 Is Essential in the Functions of B Cell and Several Fc Receptors
Wang, D., Feng, J., Wen, R., Marine, J.-C., Sangster, M. Y., Parganas, E., Hoffmeyer, A., Jackson, C. W., Cleveland, J. L., Murray, P. J., et al. (2000) · Immunity · doi:10.1016/s1074-7613(00)00005-4 · Cited by 475
Self-citationSpontaneous Skin Ulceration and Defective T Cell Function in CD18 Null Mice
Scharffetter‐Kochanek, K., Lu, H., Norman, K. E., van Nood, N., Muñoz, F. M., Grabbe, S., McArthur, M. J., Lorenzo, I., Kaplan, S. L., Ley, K. F., et al. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.1.119 · Cited by 351
Self-citationP hosphoinositide 3-K inase : Diverse Roles in Immune Cell Activation
Deane, J. A., & Fruman, D. A. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104721 · Cited by 347
Hidalgo, A., Peired, A. J., Wild, M. K., Vestweber, D., & Frenette, P. S. (2007) · Immunity · doi:10.1016/j.immuni.2007.03.011 · Cited by 324
SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond
Koretzky, G. A., Abtahian, F., & Silverman, M. A. (2006) · Nature reviews. Immunology · doi:10.1038/nri1750 · Cited by 292
Zarbock, A., Lowell, C. A., & Ley, K. F. (2007) · Immunity · doi:10.1016/j.immuni.2007.04.011 · Cited by 292
Self-citationInoue, O., Suzuki‐Inoue, K., Dean, W. L., Frampton, J., & Watson, S. P. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200208043 · Cited by 246
Integrin modulation and signaling in leukocyte adhesion and migration
Rose, D. M., Alon, R., & Ginsberg, M. H. (2007) · Immunological Reviews · doi:10.1111/j.1600-065x.2007.00536.x · Cited by 243
Simon, S. I., Hu, Y., Vestweber, D., & Smith, C. W. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.8.4348 · Cited by 238
Xia, L., Sperandio, M., Yago, T., McDaniel, J. M., Cummings, R. D., Pearson-White, S. H., Ley, K. F., & McEver, R. P. (2002) · Journal of Clinical Investigation · doi:10.1172/jci14151 · Cited by 230
Self-citationBTK Regulates PtdIns-4,5-P2 Synthesis
Saito, K., Tolias, K. F., Saci, A., Koon, H. B., Humphries, L. A., Scharenberg, A. M., Rawlings, D. J., Kinet, J.-P., & Carpenter, C. L. (2003) · Immunity · doi:10.1016/s1074-7613(03)00297-8 · Cited by 214
Urzainqui, A., Serrador, J. M., Viedma, F., Yáñez‐Mó, M., Rodrı́guez, A., Corbí, A. L., Alonso-Lebrero, J. L., Luque, A., Deckert, M., Vázquez, J., et al. (2002) · Immunity · doi:10.1016/s1074-7613(02)00420-x · Cited by 212
de Weers, M., Verschuren, M. C. M., Kraakman, M. E. M., Mensink, R. G. J., Schuurman, R. K. B., van Dongen, J. J. M., & Hendriks, R. W. (1993) · European Journal of Immunology · doi:10.1002/eji.1830231210 · Cited by 202
Zarbock, A., Abram, C. L., Hundt, M., Altman, A., Lowell, C. A., & Ley, K. F. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20072660 · Cited by 201
Self-citationCD44 is a physiological E-selectin ligand on neutrophils
Katayama, Y., Hidalgo, A., Chang, J., Peired, A. J., & Frenette, P. S. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20042014 · Cited by 200
Control of leukocyte rolling velocity in TNF-α–induced inflammation by LFA-1 and Mac-1
Dunne, J. L., Ballantyne, C. M., Beaudet, A. L., & Ley, K. F. (2002) · Blood · doi:10.1182/blood.v99.1.336 · Cited by 200
Self-citationXia, L., Sperandio, M., Yago, T., McDaniel, J. M., Cummings, R. D., Pearson-White, S. H., Ley, K. F., & McEver, R. P. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0214151 · Cited by 199
Self-citationSalas, A., Shimaoka, M., Kogan, A. N., Harwood, C. M., von Andrian, U. H., & Springer, T. A. (2004) · Immunity · doi:10.1016/s1074-7613(04)00082-2 · Cited by 193
P-selectin primes leukocyte integrin activation during inflammation
Wang, H.-B., Wang, J.-T., Zhang, L., Geng, Z. H., Xu, W.-L., Xu, T., Huo, Y., Zhu, X., Plow, E. F., Chen, M., et al. (2007) · Nature Immunology · doi:10.1038/ni1491 · Cited by 169
Regulation of B Lymphocyte Development and Activation by Bruton's Tyrosine Kinase
Khan, W. N. (2001) · Immunologic Research · doi:10.1385/ir:23:2-3:147 · Cited by 156
Regulation of phospholipase C γ isoforms in haematopoietic cells
Wilde, J. I., & Watson, S. P. (2001) · Cellular Signalling · doi:10.1016/s0898-6568(01)00191-7 · Cited by 149
Selective role of PI3Kδ in neutrophil inflammatory responses
Sadhu, C., Dick, K. O., Tino, W. T., & Staunton, D. E. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)01480-3 · Cited by 142
A Critical Role for Phospholipase Cγ2 in αIIbβ3-mediated Platelet Spreading
Wonerow, P., Pearce, A. C., Vaux, D. J., & Watson, S. P. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305077200 · Cited by 138
CXCR2- and E-Selectin–induced Neutrophil Arrest during Inflammation In Vivo
Smith, M. L., Olson, T. S., & Ley, K. F. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040424 · Cited by 138
Self-citationMangla, A. G., Khare, A., Varanasi, V., Panday, N. N., Mukhopadhyay, A., Ravindran, B., Bal, V., George, A., & Rath, S. (2004) · Blood · doi:10.1182/blood-2004-01-0207 · Cited by 128
Graham, D. B., Robertson, C. M., Bautista, J., Mascarenhas, F., Diacovo, M. J., Montgrain, V., Lam, S. K., Cremasco, V., Dunne, W. M., Faccio, R., et al. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32729 · Cited by 124
Jakus, Z., Simon, E., Frommhold, D., Sperandio, M., & Mócsai, A. (2009) · Journal of Experimental Medicine · doi:10.1084/jem.20081859 · Cited by 119
Dekker, L. V., & Segal, A. W. (2000) · Science · doi:10.1126/science.287.5455.982 · Cited by 112
Miner, J. J., Xia, L., Yago, T., Kappelmayer, J., Liu, Z., Kłopocki, A. G., Shao, B., McDaniel, J. M., Setiadi, H., Schmidtke, D. W., et al. (2008) · Blood · doi:10.1182/blood-2008-04-149468 · Cited by 102
Leukocyte PI3Kγ and PI3Kδ have temporally distinct roles for leukocyte recruitment in vivo
Liu, L., Puri, K. D., Penninger, J. M., & Kubes, P. (2007) · Blood · doi:10.1182/blood-2006-11-060103 · Cited by 100
Mempel, T. R., Moser, C., Hutter, J., Kuebler, W. M., & Krombach, F. (2003) · Journal of Vascular Research · doi:10.1159/000073902 · Cited by 88
Smith, D. F., Deem, T. L., Bruce, A. C., Reutershan, J., Wu, D. D., & Ley, K. F. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.0306227 · Cited by 82
Self-citationGilbert, C., Levasseur, S., Desaulniers, P., Dusseault, A.-A., Thibault, N., Bourgoin, S. G., & Naccache, P. H. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.10.5235 · Cited by 77
Chemotactic Factor-induced Recruitment and Activation of Tec Family Kinases in Human Neutrophils
Lachance, G., Levasseur, S., & Naccache, P. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201903200 · Cited by 74
Müller, S., Sideras, P., Smith, C. I., & Xanthopoulos, K. G. (1996) · PubMed · Cited by 63
Schaff, U. Y., Mattila, P. E., Simon, S. I., & Walcheck, B. K. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0507304 · Cited by 43
CD11b/CD18-coated microspheres attach to E-selectin under flow
Crutchfield, K. L., Patil, V. R. S., Campbell, C. J., Parkos, C. A., Allport, J. R., & Goetz, D. J. (2000) · Journal of Leukocyte Biology · doi:10.1002/jlb.67.2.196 · Cited by 41
Matsumoto, M., Shigeta, A., Miyasaka, M., & Hirata, T. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.5.3628 · Cited by 31
Signal transduction - Signals to move cells
Dekker, L. V., & Segal, A. W. (2000) · UCL Discovery (University College London) · Cited by 28
Cited by
Sorted by citations
Neutrophil Function: From Mechanisms to Disease
Amulic, B., Cazalet, C., Hayes, G. L., Metzler, K. D., & Zychlinsky, A. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-074942 · Cited by 1,782
Neutrophils, from Marrow to Microbes
Borregaard, N. (2010) · Immunity · doi:10.1016/j.immuni.2010.11.011 · Cited by 1,679
Role of Bruton’s tyrosine kinase in B cells and malignancies
Pal Singh, S., Dammeijer, F., & Hendriks, R. W. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0779-z · Cited by 726
Neutrophil cell surface receptors and their intracellular signal transduction pathways
Futosi, K., Fodor, S., & Mócsai, A. (2013) · International Immunopharmacology · doi:10.1016/j.intimp.2013.06.034 · Cited by 642
Selectins: initiators of leucocyte adhesion and signalling at the vascular wall
McEver, R. P. (2015) · Cardiovascular Research · doi:10.1093/cvr/cvv154 · Cited by 575
Metadata
- Authors
- Mueller, H., Stadtmann, A., Van Aken, H., Hirsch, E., Wang, D., Ley, K., & Zarbock, A.
- Affiliations
- Max Planck Society (DE)
- Department of Anesthesiology and Intensive Care Medicine, University of Münster, Münster, Germany;
- University of Turin (IT)
- Versiti Blood Center of Wisconsin (US)
- La Jolla Institute for Immunology (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-04-15
- Volume
- 115
- Issue
- 15
- Pages
- 3118-3127
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2858472
- OpenAlex
- W2102637482
- Cited by
- 164
- References
- 51
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 8 · 2021: 11 · 2020: 7 · 2019: 9 · 2018: 13 · 2017: 7 · 2016: 11 · 2015: 11 · 2014: 8 · 2013: 14 · 2012: 18
- FWCI
- 11.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medicine
- National Institute of Allergy and Infectious Diseases (R01AI079087)
- Topics
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Keywords
- Bruton's tyrosine kinase, E-selectin, integrin activation, neutrophil recruitment, PLCγ2, PI3Kγ, Syk signaling, leukocyte rolling, leukocyte adhesion, transmigration, inositol trisphosphate, Tec family kinases, peritonitis, cremaster muscle
- MeSH terms
- Agammaglobulinaemia Tyrosine Kinase, Animals, Cell Adhesion, Enzyme Activation, Mice, Inbred C57BL, Neutrophils, Phosphorylation, Protein-Tyrosine Kinases, Signal Transduction, CD18 Antigens, Chemokines, E-Selectin, GTP-Binding Protein alpha Subunits, Gi-Go, Phosphatidylinositol 3-Kinases, Neutrophil Infiltration, Leukocyte Rolling, p38 Mitogen-Activated Protein Kinases, Mice, Phospholipase C gamma
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
