scholarly journals The importance of Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons sterile-α motif domain in thymic selection and T-cell activation

Blood ◽  
2009 ◽  
Vol 114 (1) ◽  
pp. 74-84 ◽  
Author(s):  
Shudan Shen ◽  
Jasmine Lau ◽  
Minghua Zhu ◽  
Jianwei Zou ◽  
Deirdre Fuller ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Thymic Selection ◽  
Thymocyte Development ◽  
Sam Domain ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain

Abstract The Src homology 2 domain–containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76) is a cytosolic adaptor protein essential for thymocyte development and T-cell activation. It contains a sterile-α motif (SAM) domain, 3 phosphotyrosine motifs, a proline-rich region, and a Src homology 2 domain. Whereas the other domains have been extensively studied, the role of the SAM domain in SLP-76 function is not known. To understand the function of this domain, we generated SLP-76 knockin mice with the SAM domain deleted. Analysis of these mice showed that thymocyte development was partially blocked at the double-positive to single-positive transition. Positive and negative thymic selection was also impaired. In addition, we analyzed T-cell receptor (TCR)–mediated signaling in T cells from these mutant mice. TCR-mediated inositol 1,4,5-triphosphate production, calcium flux, and extracellular signal-regulated kinase activation were decreased, leading to defective interleukin-2 production and proliferation. Moreover, despite normal association between Gads and SLP-76, TCR-mediated formation of SLP-76 microclusters was impaired by the deletion of the SAM domain. Altogether, our data demonstrated that the SAM domain is indispensable for optimal SLP-76 signaling.

scholarly journals Involvement of Src-homology-2-domain-containing Protein-tyrosine Phosphatase 2 in T Cell Activation

1996 ◽  
Vol 237 (3) ◽  
pp. 736-742 ◽  
Author(s):  
Pankaj Tailor ◽  
Thomas Jascur ◽  
Scott Williams ◽  
Maria Willebrand ◽  
Clement Couture ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Protein Tyrosine Phosphatase ◽  
Cell Activation ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain

scholarly journals Cytokine-Induced Src Homology 2 Protein (Cis) Promotes T Cell Receptor–Mediated Proliferation and Prolongs Survival of Activated T Cells

2000 ◽  
Vol 191 (6) ◽  
pp. 985-994 ◽  
Author(s):  
Suling Li ◽  
Shangwu Chen ◽  
Xiufeng Xu ◽  
Anette Sundstedt ◽  
Kajsa M. Paulsson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cell Receptor ◽  
Cytokine Signaling ◽  
Src Homology 2 ◽  
Src Homology

Members of the suppressor of cytokine signaling (SOCS) family were discovered as negative regulators of cytokine signaling by inhibition of the Janus kinase–signal transducer and activator of transcription (Jak-STAT) pathway. Among them, cytokine-induced Src homology 2 (SH2) protein (CIS) was found to inhibit the interleukin 3– and erythropietin-mediated STAT5 signaling pathway. However, involvement of SOCS proteins in other signaling pathways is still unknown. This study shows that the expression of CIS is selectively induced in T cells after T cell receptor (TCR) stimulation. In transgenic mice, with selective expression of CIS in CD4 T cells, elevated CIS strongly promotes TCR-mediated proliferation and cytokine production in vitro, and superantigen-induced T cell activation in vivo. Forced expression of CIS also prolongs survival of CD4 T cells after TCR activation. Molecular events immediately downstream from the TCR are not changed in CIS-expressing CD4 T cells, but activation of mitogen-activated protein (MAP) kinase pathways by TCR stimulation is significantly enhanced. Together with the increased MAP kinase activation, a direct interaction of CIS and protein kinase Cθ was also demonstrated. These results suggest that CIS is one of the important regulators of TCR-mediated T cell activation. The functions of CIS, enhancing TCR signaling and inhibiting cytokine signaling, may be important in the regulation of immune response and homeostasis.

scholarly journals The N terminus of SKAP55 enables T cell adhesion to TCR and integrin ligands via distinct mechanisms

2013 ◽  
Vol 203 (6) ◽  
pp. 1021-1041 ◽  
Author(s):  
Michael J. Ophir ◽  
Beiyun C. Liu ◽  
Stephen C. Bunnell
Keyword(s):  
Cell Adhesion ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Cell Receptor ◽  
Β1 Integrins ◽  
Src Homology ◽  
Integrin Ligands ◽  
T Cell Adhesion

The T cell receptor (TCR) triggers the assembly of “SLP-76 microclusters,” which mediate signals required for T cell activation. In addition to regulating integrin activation, we show that Src kinase–associated phosphoprotein of 55 kD (SKAP55) is required for microcluster persistence and movement, junctional stabilization, and integrin-independent adhesion via the TCR. These functions require the dimerization of SKAP55 and its interaction with the adaptor adhesion and degranulation-promoting adaptor protein (ADAP). A “tandem dimer” containing two ADAP-binding SKAP55 Src homology 3 (SH3) domains stabilized SLP-76 microclusters and promoted T cell adhesion via the TCR, but could not support adhesion to integrin ligands. Finally, the SKAP55 dimerization motif (DM) enabled the coimmunoprecipitation of the Rap1-dependent integrin regulator Rap1-GTP–interacting adaptor molecule (RIAM), the recruitment of talin into TCR-induced adhesive junctions, and “inside-out” signaling to β1 integrins. Our data indicate that SKAP55 dimers stabilize SLP-76 microclusters, couple SLP-76 to the force-generating systems responsible for microcluster movement, and enable adhesion via the TCR by mechanisms independent of RIAM, talin, and β1 integrins.

scholarly journals The kinase, SH3, and SH2 domains of Lck play critical roles in T-cell activation after ZAP-70 membrane localization.

1996 ◽  
Vol 16 (12) ◽  
pp. 7151-7160 ◽  
Author(s):  
S Yamasaki ◽  
M Takamatsu ◽  
M Iwashima
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Tyrosine Kinases ◽  
Cell Activation ◽  
Chimeric Protein ◽  
Activated T Cells ◽  
Sh2 Domains ◽  
Src Homology 2 ◽  
Src Homology ◽  
Signaling Process

Antigenic stimulation of the T-cell antigen receptor initiates signal transduction through the immunoreceptor tyrosine-based activation motifs (ITAMs). When its two tyrosines are phosphorylated, ITAM forms a binding site for ZAP-70, one of the cytoplasmic protein tyrosine kinases essential for T-cell activation. The signaling process that follows ZAP-70 binding to ITAM has been analyzed by the construction of fusion proteins that localize ZAP-70 to the plasma membrane. We found that membrane-localized forms of ZAP-70 induce late signaling events such as activation of nuclear factor of activated T cells without any stimulation. This activity was observed only when Lck was expressed and functional. In addition, each mutation that affects the function of Lck in the kinase, Src homology 2 (SH2), and SH3 domains greatly impaired the signaling ability of the chimeric protein. Therefore, Lck functions in multiple manners in T-cell activation for the steps following ZAP-70 binding to ITAM.

scholarly journals LIME, a Novel Transmembrane Adaptor Protein, Associates with p56lck and Mediates T Cell Activation

2003 ◽  
Vol 198 (10) ◽  
pp. 1463-1473 ◽  
Author(s):  
Eun Mi Hur ◽  
Myoungsun Son ◽  
Ok-Hee Lee ◽  
Young Bong Choi ◽  
Changwon Park ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Transcriptional Activation ◽  
Cell Activation ◽  
Transmembrane Domain ◽  
Adaptor Protein ◽  
Jurkat T Cells ◽  
Downstream Signaling ◽  
Src Homology

In this study, we identify and characterize a novel transmembrane adaptor protein, designated Lck-interacting membrane protein (LIME), as a binding partner of the Lck Src homology (SH)2 domain. LIME possesses a short extracellular domain, a transmembrane domain, and a cytoplasmic tail containing five tyrosine-based motifs. The protein is primarily expressed in hematopoietic cells and lung. Interestingly, LIME expression is up-regulated by TCR stimulation and sustained up to 24 h, suggesting that LIME acts throughout the early to late stages of T cell activation. LIME is localized to membrane rafts and distributed within the T cell–APC contact site. Upon TCR stimulation of Jurkat T cells, LIME associates with Lck as a tyrosine-phosphorylated protein. Experiments using Jurkat T cells expressing CD8–LIME chimera reveal that the protein associates with phosphatidylinositol 3-kinase, Grb2, Gads, and SHP2, and activates ERK1/2 and JNK but not p38. Moreover, overexpression of LIME in Jurkat T cells induces transcriptional activation of the IL-2 promoter. Our data collectively show that LIME is a raft-associated transmembrane adaptor protein linking TCR stimuli to downstream signaling pathways via associations with Lck.

scholarly journals Molecular Cloning of the cDNA Encoding pp36, a Tyrosine-phosphorylated Adaptor Protein Selectively Expressed by T Cells and Natural Killer Cells

1998 ◽  
Vol 187 (7) ◽  
pp. 1157-1161 ◽  
Author(s):  
John R. Weber ◽  
Sigurd Ørstavik ◽  
Knut Martin Torgersen ◽  
Niels Christian Danbolt ◽  
Siri F. Berg ◽  
...  
Keyword(s):  
Natural Killer ◽  
Molecular Cloning ◽  
Cell Activation ◽  
Nk Cell ◽  
Rabbit Antiserum ◽  
Adaptor Protein ◽  
Peptide Sequence ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain

Activation of T and natural killer (NK) cells leads to the tyrosine phosphorylation of pp36 and to its association with several signaling molecules, including phospholipase Cγ-1 and Grb2. Microsequencing of peptides derived from purified rat pp36 protein led to the cloning, in rat and man, of cDNA encoding a T- and NK cell–specific protein with several putative Src homology 2 domain–binding motifs. A rabbit antiserum directed against a peptide sequence from the cloned rat molecule recognized tyrosine phosphorylated pp36 from pervanadate-treated rat thymocytes. When expressed in 293T human fibroblast cells and tyrosine-phosphorylated, pp36 associated with phospholipase Cγ-1 and Grb2. Studies with GST–Grb2 fusion proteins demonstrated that the association was specific for the Src homology 2 domain of Grb-2. Molecular cloning of the gene encoding pp36 should facilitate studies examining the role of this adaptor protein in proximal signaling events during T and NK cell activation.

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