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Science 292 (5522): 1681-1686

Copyright © 2001 by the American Association for the Advancement of Science

Physiological Regulation of the Immunological Synapse by Agrin

Adil A. Khan,12* Christian Bose,2 Lung S. Yam,2 Mark J. Soloski,3 Fabio Rupp2dagger

T cell activation is dependent on both a primary signal delivered through the T cell receptor and a secondary costimulatory signal mediated by coreceptors. Although controversial, costimulation is thought to act through the specific redistribution and clustering of membrane and intracellular kinase-rich lipid raft microdomains at the contact site between T cells and antigen-presenting cells. This site has been termed the immunological synapse. Endogenous mediators of raft clustering in lymphocytes have not been identified, although they are essential for T cell activation. We now demonstrate that agrin, an aggregating protein crucial for formation of the neuromuscular junction, is also expressed in lymphocytes and is important in reorganization of membrane lipid microdomains and setting the threshold for T cell signaling. Our data show that agrin induces the aggregation of signaling proteins and the creation of signaling domains in both immune and nervous systems through a common lipid raft pathway.

1 Outer Banks Neuroscience, Baltimore, MD 21218, USA.
2 Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
3 Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
*   To whom correspondence should be addressed: outerbanksneuro{at}

dagger    Present address: Hyseq Inc., Sunnyvale, CA 94085, USA.

Agrin is required for survival and function of monocytic cells.
C. Mazzon, A. Anselmo, C. Soldani, J. Cibella, C. Ploia, F. Moalli, S. J. Burden, M. L. Dustin, A. Sarukhan, and A. Viola (2012)
Blood 119, 5502-5511
   Abstract »    Full Text »    PDF »
Agrin complicates the niche.
L. M. Calvi (2011)
Blood 118, 2641-2642
   Full Text »    PDF »
The critical role of agrin in the hematopoietic stem cell niche.
C. Mazzon, A. Anselmo, J. Cibella, C. Soldani, A. Destro, N. Kim, M. Roncalli, S. J. Burden, M. L. Dustin, A. Sarukhan, et al. (2011)
Blood 118, 2733-2742
   Abstract »    Full Text »    PDF »
Heparan Sulfate Modification of the Transmembrane Receptor CD47 Is Necessary for Inhibition of T Cell Receptor Signaling by Thrombospondin-1.
S. Kaur, S. A. Kuznetsova, M. L. Pendrak, J. M. Sipes, M. J. Romeo, Z. Li, L. Zhang, and D. D. Roberts (2011)
J. Biol. Chem. 286, 14991-15002
   Abstract »    Full Text »    PDF »
Asparagine of z8 Insert Is Critical for the Affinity, Conformation, and Acetylcholine Receptor-clustering Activity of Neural Agrin.
C.-N. Tseng, L. Zhang, S.-L. Wu, W.-F. Wang, Z.-Z. Wang, and M. Cascio (2010)
J. Biol. Chem. 285, 27641-27651
   Abstract »    Full Text »    PDF »
Interdependence of Laminin-mediated Clustering of Lipid Rafts and the Dystrophin Complex in Astrocytes.
G. Noel, D. K. L. Tham, and H. Moukhles (2009)
J. Biol. Chem. 284, 19694-19704
   Abstract »    Full Text »    PDF »
Transmembrane Form Agrin-induced Process Formation Requires Lipid Rafts and the Activation of Fyn and MAPK.
R. Ramseger, R. White, and S. Kroger (2009)
J. Biol. Chem. 284, 7697-7705
   Abstract »    Full Text »    PDF »
Binding of laminin-1 to monosialoganglioside GM1 in lipid rafts is crucial for neurite outgrowth.
N. Ichikawa, K. Iwabuchi, H. Kurihara, K. Ishii, T. Kobayashi, T. Sasaki, N. Hattori, Y. Mizuno, K. Hozumi, Y. Yamada, et al. (2009)
J. Cell Sci. 122, 289-299
   Abstract »    Full Text »    PDF »
Agrin Signalling Contributes to Cell Activation and Is Overexpressed in T Lymphocytes from Lupus Patients.
E. C. Jury, J. Eldridge, D. A. Isenberg, and P. S. Kabouridis (2007)
J. Immunol. 179, 7975-7983
   Abstract »    Full Text »    PDF »
Structural and Functional Characterization of a Novel T Cell Receptor Co-regulatory Protein Complex, CD97-CD55.
R. J. M. Abbott, I. Spendlove, P. Roversi, H. Fitzgibbon, V. Knott, P. Teriete, J. M. McDonnell, P. A. Handford, and S. M. Lea (2007)
J. Biol. Chem. 282, 22023-22032
   Abstract »    Full Text »    PDF »
Activation of Muscle-specific Receptor Tyrosine Kinase and Binding to Dystroglycan Are Regulated by Alternative mRNA Splicing of Agrin.
P. Scotton, D. Bleckmann, M. Stebler, F. Sciandra, A. Brancaccio, T. Meier, J. Stetefeld, and M. A. Ruegg (2006)
J. Biol. Chem. 281, 36835-36845
   Abstract »    Full Text »    PDF »
Functional Implication of Cellular Prion Protein in Antigen-Driven Interactions between T Cells and Dendritic Cells.
C. Ballerini, P. Gourdain, V. Bachy, N. Blanchard, E. Levavasseur, S. Gregoire, P. Fontes, P. Aucouturier, C. Hivroz, and C. Carnaud (2006)
J. Immunol. 176, 7254-7262
   Abstract »    Full Text »    PDF »
Imatinib mesylate minimally affects bcr-abl+ and normal monocyte-derived dendritic cells but strongly inhibits T cell expansion despite reciprocal dendritic cell-T cell activation.
N. Boissel, P. Rousselot, E. Raffoux, J.-M. Cayuela, J. Soulier, N. Mooney, D. Charron, H. Dombret, A. Toubert, and D. Rea (2006)
J. Leukoc. Biol. 79, 747-756
   Abstract »    Full Text »    PDF »
Agrin is involved in lymphocytes activation that is mediated by {alpha}-dystroglycan.
J. Zhang, Y. Wang, Y. Chu, L. Su, Y. Gong, R. Zhang, and S. Xiong (2006)
FASEB J 20, 50-58
   Abstract »    Full Text »    PDF »
HIV-1-infected Blood Mononuclear Cells Form an Integrin- and Agrin-dependent Viral Synapse to Induce Efficient HIV-1 Transcytosis across Epithelial Cell Monolayer.
A. Alfsen, H. Yu, A. Magerus-Chatinet, A. Schmitt, and M. Bomsel (2005)
Mol. Biol. Cell 16, 4267-4279
   Abstract »    Full Text »    PDF »
Analysis of host response to bacterial infection using error model based gene expression microarray experiments.
D. J. Stekel, D. Sarti, V. Trevino, L. Zhang, M. Salmon, C. D. Buckley, M. Stevens, M. J. Pallen, C. Penn, and F. Falciani (2005)
Nucleic Acids Res. 33, e53
   Abstract »    Full Text »    PDF »
Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells.
J. L. Round, T. Tomassian, M. Zhang, V. Patel, S. P. Schoenberger, and M. C. Miceli (2005)
J. Exp. Med. 201, 419-430
   Abstract »    Full Text »    PDF »
A Single Pulse of Agrin Triggers a Pathway That Acts To Cluster Acetylcholine Receptors.
P. Mittaud, A. A. Camilleri, R. Willmann, S. Erb-Vogtli, S. J. Burden, and C. Fuhrer (2004)
Mol. Cell. Biol. 24, 7841-7854
   Abstract »    Full Text »    PDF »
Thy-1: More than a Mouse Pan-T Cell Marker.
S. M. M. Haeryfar and D. W. Hoskin (2004)
J. Immunol. 173, 3581-3588
   Abstract »    Full Text »    PDF »
The LFA-1-associated Molecule PTA-1 (CD226) on T Cells Forms a Dynamic Molecular Complex with Protein 4.1G and Human Discs Large.
K. J. Ralston, S. L. Hird, X. Zhang, J. L. Scott, B. Jin, R. F. Thorne, M. C. Berndt, A. W. Boyd, and G. F. Burns (2004)
J. Biol. Chem. 279, 33816-33828
   Abstract »    Full Text »    PDF »
Homer-3 regulates activation of serum response element in T cells via its EVH1 domain.
K. Ishiguro and R. Xavier (2004)
Blood 103, 2248-2256
   Abstract »    Full Text »    PDF »
Analysis of the Mobility of Signaling Molecules in Lymphocytes Using Fluorescence Photobleaching Techniques.
N. Tanimura, M. Nagafuku, D. R. Liddicoat, T. Hamaoka, and A. Kosugi (2003)
Sci. STKE 2003, pl10
   Abstract »    Full Text »    PDF »
T-Cell Responses to CD1-Presented Lipid Antigens in Humans with Mycobacterium tuberculosis Infection.
T. Ulrichs, D. B. Moody, E. Grant, S. H. E. Kaufmann, and S. A. Porcelli (2003)
Infect. Immun. 71, 3076-3087
   Abstract »    Full Text »    PDF »
Visualizing Lipid Raft Dynamics and Early Signaling Events during Antigen Receptor-mediated B-Lymphocyte Activation.
N. Gupta and A. L. DeFranco (2003)
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   Abstract »    Full Text »    PDF »
A Role for the Juxtamembrane Domain of beta -Dystroglycan in Agrin-Induced Acetylcholine Receptor Clustering.
J. Kahl and J. T. Campanelli (2003)
J. Neurosci. 23, 392-402
   Abstract »    Full Text »    PDF »
Dynamic changes in the mobility of LAT in aggregated lipid rafts upon T cell activation.
N. Tanimura, M. Nagafuku, Y. Minaki, Y. Umeda, F. Hayashi, J. Sakakura, A. Kato, D. R. Liddicoat, M. Ogata, T. Hamaoka, et al. (2003)
J. Cell Biol. 160, 125-135
   Abstract »    Full Text »    PDF »
HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells.
A. Skaletz-Rorowski, M. Lutchman, Y. Kureishi, D. J. Lefer, J. R. Faust, and K. Walsh (2003)
Cardiovasc Res 57, 253-264
   Abstract »    Full Text »    PDF »
Characterization of the Acid Stability of Glycosidically Linked Neuraminic Acid. USE IN DETECTING DE-N-ACETYL-GANGLIOSIDES IN HUMAN MELANOMA.
J. L. Sonnenburg, H. van Halbeek, and A. Varki (2002)
J. Biol. Chem. 277, 17502-17510
   Abstract »    Full Text »    PDF »
Neuronal activity-dependent membrane traffic at the neuromuscular junction.
F. J. Miana-Mena, S. Roux, J.-C. Benichou, R. Osta, and P. Brulet (2002)
PNAS 99, 3234-3239
   Abstract »    Full Text »    PDF »
Rafts and synapses in the spatial organization of immune cell signaling receptors.
M. Dykstra, A. Cherukuri, and S. K. Pierce (2001)
J. Leukoc. Biol. 70, 699-707
   Abstract »    Full Text »    PDF »

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