scholarly journals Targeting Src Homology 2 Domain-Containing Tyrosine Phosphatase (SHP-1) into Lipid Rafts Inhibits CD3-Induced T Cell Activation

2001 ◽  
Vol 166 (6) ◽  
pp. 3975-3982 ◽  
Author(s):  
Michael Wei-Chih Su ◽  
Chao-Lan Yu ◽  
Steven J. Burakoff ◽  
Yong-Jiu Jin
Keyword(s):  
T Cell ◽  
Lipid Rafts ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tyrosine Phosphatase ◽  
Src Homology 2 ◽  
Src Homology ◽  
Src Homology 2 Domain

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 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 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 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 PD-1 suppresses TCR-CD8 cooperativity during T-cell antigen recognition

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kaitao Li ◽  
Zhou Yuan ◽  
Jintian Lyu ◽  
Eunseon Ahn ◽  
Simon J. Davis ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Clinical Success ◽  
Clinical Intervention ◽  
Cell Receptor ◽  
Cell Interaction ◽  
Antigen Recognition ◽  
Inhibitory Function ◽  
Src Homology

AbstractDespite the clinical success of blocking its interactions, how PD-1 inhibits T-cell activation is incompletely understood, as exemplified by its potency far exceeding what might be predicted from its affinity for PD-1 ligand-1 (PD-L1). This may be partially attributed to PD-1’s targeting the proximal signaling of the T-cell receptor (TCR) and co-stimulatory receptor CD28 via activating Src homology region 2 domain-containing phosphatases (SHPs). Here, we report PD-1 signaling regulates the initial TCR antigen recognition manifested in a smaller spreading area, fewer molecular bonds formed, and shorter bond lifetime of T cell interaction with peptide-major histocompatibility complex (pMHC) in the presence than absence of PD-L1 in a manner dependent on SHPs and Leukocyte C-terminal Src kinase. Our results identify a PD-1 inhibitory mechanism that disrupts the cooperative TCR–pMHC–CD8 trimolecular interaction, which prevents CD8 from augmenting antigen recognition, explaining PD-1’s potent inhibitory function and its value as a target for clinical intervention.

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