Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 21 September 2001:
Vol. 293. no. 5538, pp. 2260 - 2263
DOI: 10.1126/science.1063397
Prev | Table of Contents | Next

Reports

Positive Regulation of T Cell Activation and Integrin Adhesion by the Adapter Fyb/Slap

Emily K. Griffiths,12 Connie Krawczyk,12 Young-Yun Kong,12 Monika Raab,3 Sharon J. Hyduk,4 Denis Bouchard,1 Vera S. Chan,2 Ivona Kozieradzki,12 Antonio J. Oliveira-dos-Santos,12 Andrew Wakeham,1 Pamela S. Ohashi,2 Myron I. Cybulsky,4 Christopher E. Rudd,3 Josef M. Penninger12*

The molecular adapter Fyb/Slap regulates signaling downstream of the T cell receptor (TCR), but whether it plays a positive or negative role is controversial. We demonstrate that Fyb/Slap-deficient T cells exhibit defective proliferation and cytokine production in response to TCR stimulation. Fyb/Slap is also required in vivo for T cell-dependent immune responses. Functionally, Fyb/Slap has no apparent role in the activation of known TCR signaling pathways, F-actin polymerization, or TCR clustering. Rather, Fyb/Slap regulates TCR-induced integrin clustering and adhesion. Thus, Fyb/Slap is the first molecular adapter to be identified that couples TCR stimulation to the avidity modulation of integrins governing T cell adhesion.

1 Amgen Institute, 620 University Avenue, Toronto, Ontario, Canada M5G 2C1.
2 Ontario Cancer Institute, University Health Network, and Departments of Medical Biophysics and Immunology, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9.
3 Division of Tumor Immunology, Dana-Farber Cancer Institute, and Departments of Pathology and Medicine, Harvard Medical School, Boston, MA 02115, USA.
4 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto General Hospital Research Institute, Toronto, Canada.
*   To whom correspondence should be addressed. E-mail: jpenning{at}amgen.com

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Src Homology 2-Domain Containing Leukocyte-Specific Phosphoprotein of 76 kDa Is Mandatory for TCR-Mediated Inside-Out Signaling, but Dispensable for CXCR4-Mediated LFA-1 Activation, Adhesion, and Migration of T Cells.
J. Horn, X. Wang, P. Reichardt, T. E. Stradal, N. Warnecke, L. Simeoni, M. Gunzer, D. Yablonski, B. Schraven, and S. Kliche (2009)
J. Immunol. 183, 5756-5767
   Abstract »    Full Text »    PDF »
The Adapter Protein SLP-76 Mediates "Outside-In" Integrin Signaling and Function in T Cells.
R. G. Baker, C. J. Hsu, D. Lee, M. S. Jordan, J. S. Maltzman, D. A. Hammer, T. Baumgart, and G. A. Koretzky (2009)
Mol. Cell. Biol. 29, 5578-5589
   Abstract »    Full Text »    PDF »
SLP-76-ADAP adaptor module regulates LFA-1 mediated costimulation and T cell motility.
H. Wang, B. Wei, G. Bismuth, and C. E. Rudd (2009)
PNAS 106, 12436-12441
   Abstract »    Full Text »    PDF »
Expression of SKAP-HOM in DCs is required for an optimal immune response in vivo.
A. Reinhold, S. Reimann, D. Reinhold, B. Schraven, and M. Togni (2009)
J. Leukoc. Biol. 86, 61-71
   Abstract »    Full Text »    PDF »
Cytohesin-1 controls the activation of RhoA and modulates integrin-dependent adhesion and migration of dendritic cells.
T. Quast, B. Tappertzhofen, C. Schild, J. Grell, N. Czeloth, R. Forster, R. Alon, L. Fraemohs, K. Dreck, C. Weber, et al. (2009)
Blood 113, 5801-5810
   Abstract »    Full Text »    PDF »
CD45 Down-Regulates Lck-Mediated CD44 Signaling and Modulates Actin Rearrangement in T Cells.
N. K. Y. Wong, J. C. Y. Lai, D. Birkenhead, A. S. Shaw, and P. Johnson (2008)
J. Immunol. 181, 7033-7043
   Abstract »    Full Text »    PDF »
Distinct Regulation of Integrin-Dependent T Cell Conjugate Formation and NF-{kappa}B Activation by the Adapter Protein ADAP.
B. J. Burbach, R. Srivastava, R. B. Medeiros, W. E. O'Gorman, E. J. Peterson, and Y. Shimizu (2008)
J. Immunol. 181, 4840-4851
   Abstract »    Full Text »    PDF »
Regulation of integrin activation through the B-cell receptor.
E. Arana, N. E. Harwood, and F. D. Batista (2008)
J. Cell Sci. 121, 2279-2286
   Abstract »    Full Text »    PDF »
{alpha}PIX Rho GTPase Guanine Nucleotide Exchange Factor Regulates Lymphocyte Functions and Antigen Receptor Signaling.
K. Missy, B. Hu, K. Schilling, A. Harenberg, V. Sakk, K. Kuchenbecker, K. Kutsche, and K.-D. Fischer (2008)
Mol. Cell. Biol. 28, 3776-3789
   Abstract »    Full Text »    PDF »
Inverse Rap1 and Phospho-ERK Expression Discriminate the Maintenance Phase of Tolerance and Priming of Antigen-Specific CD4+ T Cells In Vitro and In Vivo.
A. M. Morton, B. McManus, P. Garside, A. McI. Mowat, and M. M. Harnett (2007)
J. Immunol. 179, 8026-8034
   Abstract »    Full Text »    PDF »
Functional Defects of SKAP-55-Deficient T Cells Identify a Regulatory Role for the Adaptor in LFA-1 Adhesion.
H. Wang, H. Liu, Y. Lu, M. Lovatt, B. Wei, and C. E. Rudd (2007)
Mol. Cell. Biol. 27, 6863-6875
   Abstract »    Full Text »    PDF »
Adhesion and Degranulation-Promoting Adapter Protein (ADAP) Positively Regulates T Cell Sensitivity to Antigen and T Cell Survival.
K. L. Mueller, M. S. Thomas, B. J. Burbach, E. J. Peterson, and Y. Shimizu (2007)
J. Immunol. 179, 3559-3569
   Abstract »    Full Text »    PDF »
WAVE2 Regulates High-Affinity Integrin Binding by Recruiting Vinculin and Talin to the Immunological Synapse.
J. C. Nolz, R. B. Medeiros, J. S. Mitchell, P. Zhu, B. D. Freedman, Y. Shimizu, and D. D. Billadeau (2007)
Mol. Cell. Biol. 27, 5986-6000
   Abstract »    Full Text »    PDF »
RIAM Links the ADAP/SKAP-55 Signaling Module to Rap1, Facilitating T-Cell-Receptor-Mediated Integrin Activation.
G. Menasche, S. Kliche, E. J. H. Chen, T. E. B. Stradal, B. Schraven, and G. Koretzky (2007)
Mol. Cell. Biol. 27, 4070-4081
   Abstract »    Full Text »    PDF »
Regulation of NF-{kappa}B Activation in T Cells via Association of the Adapter Proteins ADAP and CARMA1.
R. B. Medeiros, B. J. Burbach, K. L. Mueller, R. Srivastava, J. J. Moon, S. Highfill, E. J. Peterson, and Y. Shimizu (2007)
Science 316, 754-758
   Abstract »    Full Text »    PDF »
Physiologic and aberrant regulation of memory T-cell trafficking by the costimulatory molecule CD28.
V. Mirenda, S. J. Jarmin, R. David, J. Dyson, D. Scott, Y. Gu, R. I. Lechler, K. Okkenhaug, and F. M. Marelli-Berg (2007)
Blood 109, 2968-2977
   Abstract »    Full Text »    PDF »
ADAP is required for normal {alpha}IIb{beta}3 activation by VWF/GP Ib-IX-V and other agonists.
A. Kasirer-Friede, B. Moran, J. Nagrampa-Orje, K. Swanson, Z. M. Ruggeri, B. Schraven, B. G. Neel, G. Koretzky, and S. J. Shattil (2007)
Blood 109, 1018-1025
   Abstract »    Full Text »    PDF »
Loss of Src Homology Region 2 Domain-Containing Protein Tyrosine Phosphatase-1 Increases CD8+ T Cell-APC Conjugate Formation and Is Associated with Enhanced In Vivo CTL Function.
J. G. Sathish, G. Dolton, F. G. LeRoy, and R. J. Matthews (2007)
J. Immunol. 178, 330-337
   Abstract »    Full Text »    PDF »
The actin cloud induced by LFA-1-mediated outside-in signals lowers the threshold for T-cell activation.
J.-i. Suzuki, S. Yamasaki, J. Wu, G. A. Koretzky, and T. Saito (2007)
Blood 109, 168-175
   Abstract »    Full Text »    PDF »
The ADAP/SKAP55 Signaling Module Regulates T-Cell Receptor-Mediated Integrin Activation through Plasma Membrane Targeting of Rap1..
S. Kliche, D. Breitling, M. Togni, R. Pusch, K. Heuer, X. Wang, C. Freund, A. Kasirer-Friede, G. Menasche, G. A. Koretzky, et al. (2006)
Mol. Cell. Biol. 26, 7130-7144
   Abstract »    Full Text »    PDF »
ADAP is dispensable for NK cell development and function.
L. V. Fostel, J. Dluzniewska, Y. Shimizu, B. J. Burbach, and E. J. Peterson (2006)
Int. Immunol. 18, 1305-1314
   Abstract »    Full Text »    PDF »
Adhesion- and Degranulation-Promoting Adapter Protein Is Required for Efficient Thymocyte Development and Selection..
J. N. Wu, S. Gheith, N. A. Bezman, Q.-H. Liu, L. V. Fostel, A. M. Swanson, B. D. Freedman, G. A. Koretzky, and E. J. Peterson (2006)
J. Immunol. 176, 6681-6689
   Abstract »    Full Text »    PDF »
Defective Adhesion in Tumor Infiltrating CD8+ T Cells.
M. Koneru, N. Monu, D. Schaer, J. Barletta, and A. B. Frey (2006)
J. Immunol. 176, 6103-6111
   Abstract »    Full Text »    PDF »
Regulation and Function of SKAP-55 Non-canonical Motif Binding to the SH3c Domain of Adhesion and Degranulation-promoting Adaptor Protein.
J. S. Duke-Cohan, H. Kang, H. Liu, and C. E. Rudd (2006)
J. Biol. Chem. 281, 13743-13750
   Abstract »    Full Text »    PDF »
Enhancement of LFA-1-Mediated T Cell Adhesion by Human T Lymphotropic Virus Type 1 p12I1.
S.-j. Kim, A. M. Nair, S. Fernandez, L. Mathes, and M. D. Lairmore (2006)
J. Immunol. 176, 5463-5470
   Abstract »    Full Text »    PDF »
Rap1A-Deficient T and B Cells Show Impaired Integrin-Mediated Cell Adhesion.
M. Duchniewicz, T. Zemojtel, M. Kolanczyk, S. Grossmann, J. S. Scheele, and F. J. T. Zwartkruis (2006)
Mol. Cell. Biol. 26, 643-653
   Abstract »    Full Text »    PDF »
Protein Tyrosine Phosphatase {alpha} Regulates Fyn Activity and Cbp/PAG Phosphorylation in Thymocyte Lipid Rafts.
L. Maksumova, H. T. Le, F. Muratkhodjaev, D. Davidson, A. Veillette, and C. J. Pallen (2005)
J. Immunol. 175, 7947-7956
   Abstract »    Full Text »    PDF »
Tec Kinases Regulate TCR-Mediated Recruitment of Signaling Molecules and Integrin-Dependent Cell Adhesion.
L. D. Finkelstein, Y. Shimizu, and P. L. Schwartzberg (2005)
J. Immunol. 175, 5923-5930
   Abstract »    Full Text »    PDF »
Regulation of In Vitro and In Vivo Immune Functions by the Cytosolic Adaptor Protein SKAP-HOM.
M. Togni, K. D. Swanson, S. Reimann, S. Kliche, A. C. Pearce, L. Simeoni, D. Reinhold, J. Wienands, B. G. Neel, B. Schraven, et al. (2005)
Mol. Cell. Biol. 25, 8052-8063
   Abstract »    Full Text »    PDF »
Physical and Functional Association of c-Src and Adhesion and Degranulation Promoting Adaptor Protein (ADAP) in Osteoclastogenesis in Vitro.
S. Koga, K. Yogo, K. Yoshikawa, H. Samori, M. Goto, T. Uchida, N. Ishida, and T. Takeya (2005)
J. Biol. Chem. 280, 31564-31571
   Abstract »    Full Text »    PDF »
Deficiency of ADAP/Fyb/SLAP-130 Destabilizes SKAP55 in Jurkat T Cells.
Y. Huang, D. D. Norton, P. Precht, J. L. Martindale, J. K. Burkhardt, and R. L. Wange (2005)
J. Biol. Chem. 280, 23576-23583
   Abstract »    Full Text »    PDF »
Importance of integrin LFA-1 deactivation for the generation of immune responses.
M. Semmrich, A. Smith, C. Feterowski, S. Beer, B. Engelhardt, D. H. Busch, B. Bartsch, M. Laschinger, N. Hogg, K. Pfeffer, et al. (2005)
J. Exp. Med. 201, 1987-1998
   Abstract »    Full Text »    PDF »
An essential role for SKAP-55 in LFA-1 clustering on T cells that cannot be substituted by SKAP-55R.
E.-K. Jo, H. Wang, and C. E. Rudd (2005)
J. Exp. Med. 201, 1733-1739
   Abstract »    Full Text »    PDF »
Modular Transcriptional Activity Characterizes the Initiation and Progression of Autoimmune Encephalomyelitis.
S. E. Baranzini, C. C. A. Bernard, and J. R. Oksenberg (2005)
J. Immunol. 174, 7412-7422
   Abstract »    Full Text »    PDF »
PRAM-1 Potentiates Arsenic Trioxide-induced JNK Activation.
F. M. Denis, A. Benecke, Y. Di Gioia, I. P. Touw, Y. E. Cayre, and P. G. Lutz (2005)
J. Biol. Chem. 280, 9043-9048
   Abstract »    Full Text »    PDF »
PRAM-1 Is Required for Optimal Integrin-Dependent Neutrophil Function.
R. A. Clemens, S. A. Newbrough, E. Y. Chung, S. Gheith, A. L. Singer, G. A. Koretzky, and E. J. Peterson (2004)
Mol. Cell. Biol. 24, 10923-10932
   Abstract »    Full Text »    PDF »
ADAP-SLP-76 Binding Differentially Regulates Supramolecular Activation Cluster (SMAC) Formation Relative to T Cell-APC Conjugation.
H. Wang, F. E. McCann, J. D. Gordan, X. Wu, M. Raab, T. H. Malik, D. M. Davis, and C. E. Rudd (2004)
J. Exp. Med. 200, 1063-1074
   Abstract »    Full Text »    PDF »
Gene expression profiles during human CD4+ T cell differentiation.
M. S. Lee, K. Hanspers, C. S. Barker, A. P. Korn, and J. M. McCune (2004)
Int. Immunol. 16, 1109-1124
   Abstract »    Full Text »    PDF »
Differential Requirement for Adapter Proteins Src Homology 2 Domain-Containing Leukocyte Phosphoprotein of 76 kDa and Adhesion- and Degranulation-Promoting Adapter Protein in Fc{epsilon}RI Signaling and Mast Cell Function.
J. N. Wu, M. S. Jordan, M. A. Silverman, E. J. Peterson, and G. A. Koretzky (2004)
J. Immunol. 172, 6768-6774
   Abstract »    Full Text »    PDF »
The Adapter Molecule Sin Regulates T-Cell-Receptor-Mediated Signal Transduction by Modulating Signaling Substrate Availability.
L. Xing, L. T. Donlin, R. H. Miller, and K. Alexandropoulos (2004)
Mol. Cell. Biol. 24, 4581-4592
   Abstract »    Full Text »    PDF »
Control of TCR-Mediated Activation of {beta}1 Integrins by the ZAP-70 Tyrosine Kinase Interdomain B Region and the Linker for Activation of T Cells Adapter Protein.
S. Goda, A. C. Quale, M. L. Woods, A. Felthauser, and Y. Shimizu (2004)
J. Immunol. 172, 5379-5387
   Abstract »    Full Text »    PDF »
Signaling through GP Ib-IX-V activates {alpha}IIb{beta}3 independently of other receptors.
A. Kasirer-Friede, M. R. Cozzi, M. Mazzucato, L. De Marco, Z. M. Ruggeri, and S. J. Shattil (2004)
Blood 103, 3403-3411
   Abstract »    Full Text »    PDF »
Cognate recognition of the endothelium induces HY-specific CD8+ T-lymphocyte transendothelial migration (diapedesis) in vivo.
F. M. Marelli-Berg, M. J. James, J. Dangerfield, J. Dyson, M. Millrain, D. Scott, E. Simpson, S. Nourshargh, and R. I. Lechler (2004)
Blood 103, 3111-3116
   Abstract »    Full Text »    PDF »
Enrichment of Lck in Lipid Rafts Regulates Colocalized Fyn Activation and the Initiation of Proximal Signals through TCR{alpha}{beta}.
D. Filipp, B. L. Leung, J. Zhang, A. Veillette, and M. Julius (2004)
J. Immunol. 172, 4266-4274
   Abstract »    Full Text »    PDF »
Macrophage activation and Fc{gamma} receptor-mediated signaling do not require expression of the SLP-76 and SLP-65 adaptors.
K. E. Nichols, K. Haines, P. S. Myung, S. Newbrough, E. Myers, H. Jumaa, D. J. Shedlock, H. Shen, and G. A. Koretzky (2004)
J. Leukoc. Biol. 75, 541-552
   Abstract »    Full Text »    PDF »
T-cell integrins: more than just sticking points.
N. Hogg, M. Laschinger, K. Giles, and A. McDowall (2003)
J. Cell Sci. 116, 4695-4705
   Abstract »    Full Text »    PDF »
Developmental markers of B cells are superior to those of T cells for identification of stages with distinct gene expression profiles.
R. Hoffmann, T. Seidl, L. Bruno, and M. Dugas (2003)
J. Leukoc. Biol. 74, 602-610
   Abstract »    Full Text »    PDF »
Lymphocyte Function-associated Antigen-1-mediated T Cell Adhesion Is Impaired by Low Molecular Weight Phosphotyrosine Phosphatase-dependent Inhibition of FAK Activity.
E. Giannoni, P. Chiarugi, G. Cozzi, L. Magnelli, M. L. Taddei, T. Fiaschi, F. Buricchi, G. Raugei, and G. Ramponi (2003)
J. Biol. Chem. 278, 36763-36776
   Abstract »    Full Text »    PDF »
The {beta}1 and {beta}3 Integrins Promote T Cell Receptor-mediated Cytotoxic T Lymphocyte Activation.
M.-A. Doucey, D. F. Legler, M. Faroudi, N. Boucheron, P. Baumgaertner, D. Naeher, M. Cebecauer, D. Hudrisier, C. Ruegg, E. Palmer, et al. (2003)
J. Biol. Chem. 278, 26983-26991
   Abstract »    Full Text »    PDF »
Distinct Role of ZAP-70 and Src Homology 2 Domain-Containing Leukocyte Protein of 76 kDa in the Prolonged Activation of Extracellular Signal-Regulated Protein Kinase by the Stromal Cell-Derived Factor-1{alpha}/CXCL12 Chemokine.
K. N. Kremer, T. D. Humphreys, A. Kumar, N.-X. Qian, and K. E. Hedin (2003)
J. Immunol. 171, 360-367
   Abstract »    Full Text »    PDF »
Structural Requirements of SLP-76 in Signaling via the High-Affinity Immunoglobulin E Receptor (Fc{varepsilon}RI) in Mast Cells.
A. Kettner, V. Pivniouk, L. Kumar, H. Falet, J.-S. Lee, R. Mulligan, and R. S. Geha (2003)
Mol. Cell. Biol. 23, 2395-2406
   Abstract »    Full Text »    PDF »
Presentation of Antigen by Endothelial Cells and Chemoattraction Are Required for Homing of Insulin-specific CD8+ T Cells.
A. Y. Savinov, F. S. Wong, A. C. Stonebraker, and A. V. Chervonsky (2003)
J. Exp. Med. 197, 643-656
   Abstract »    Full Text »    PDF »
{beta}1/{beta}3 integrin ligation is uncoupled from ERK1/ERK2 activation in cytotoxic T lymphocytes.
L. G. Puente and H. L. Ostergaard (2003)
J. Leukoc. Biol. 73, 391-398
   Abstract »    Full Text »    PDF »
Differential recruitment of {alpha}2{beta}1 and {alpha}4{beta}1 integrins to lipid rafts in Jurkat T lymphocytes exposed to collagen type IV and fibronectin.
B. J. Holleran, E. Barbar, M. D. Payet, and G. Dupuis (2003)
J. Leukoc. Biol. 73, 243-252
   Abstract »    Full Text »    PDF »
Differential Requirement for LAT and SLP-76 in GPVI versus T Cell Receptor Signaling.
B. A. Judd, P. S. Myung, A. Obergfell, E. E. Myers, A. M. Cheng, S. P. Watson, W. S. Pear, D. Allman, S. J. Shattil, and G. A. Koretzky (2002)
J. Exp. Med. 195, 705-717
   Abstract »    Full Text »    PDF »
Beyond calcium: new signaling pathways for Tec family kinases.
A. Takesono, L. D. Finkelstein, and P. L. Schwartzberg (2002)
J. Cell Sci. 115, 3039-3048
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)