Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling
The T cell antigen receptor (TCR) is expressed on T cells, which orchestrate adaptive immune responses. It is composed of the ligand-binding clonotypic TCRαβ heterodimer and the non-covalently bound invariant signal-transducing CD3 complex. Among the CD3 subunits, the CD3ε cytoplasmic tail contains...
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doaj-962d8c820b7a499d987b95f744e351102021-04-07T23:05:47ZengMDPI AGCells2073-44092021-04-011083483410.3390/cells10040834Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR SignalingFrederike A. Hartl0Jatuporn Ngoenkam1Esmeralda Beck-Garcia2Liz Cerqueira3Piyamaporn Wipa4Pussadee Paensuwan5Prapat Suriyaphol6Pankaj Mishra7Burkhart Schraven8Stefan Günther9Sutatip Pongcharoen10Wolfgang W. A. Schamel11Susana Minguet12Faculty of Biology, University of Freiburg, 79104 Freiburg, GermanyDepartment of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, ThailandFaculty of Biology, University of Freiburg, 79104 Freiburg, GermanyFaculty of Biology, University of Freiburg, 79104 Freiburg, GermanyDepartment of Microbiology and Parasitology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, ThailandDepartment of Optometry, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, ThailandDivision of Bioinformatics and Data Management for Research, Research Group and Research Network Division, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, ThailandPharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, University of Freiburg, 79104 Freiburg, GermanyInstitute of Molecular and Clinical Immunology and Health Campus Immunology, Infectiology and Inflammation, Medical Faculty, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, GermanyPharmaceutical Bioinformatics, Institute of Pharmaceutical Sciences, University of Freiburg, 79104 Freiburg, GermanyDivision of Immunology, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, ThailandFaculty of Biology, University of Freiburg, 79104 Freiburg, GermanyFaculty of Biology, University of Freiburg, 79104 Freiburg, GermanyThe T cell antigen receptor (TCR) is expressed on T cells, which orchestrate adaptive immune responses. It is composed of the ligand-binding clonotypic TCRαβ heterodimer and the non-covalently bound invariant signal-transducing CD3 complex. Among the CD3 subunits, the CD3ε cytoplasmic tail contains binding motifs for the Src family kinase, Lck, and the adaptor protein, Nck. Lck binds to a receptor kinase (RK) motif and Nck binds to a proline-rich sequence (PRS). Both motifs only become accessible upon ligand binding to the TCR and facilitate the recruitment of Lck and Nck independently of phosphorylation of the TCR. Mutations in each of these motifs cause defects in TCR signaling and T cell activation. Here, we investigated the role of Nck in proximal TCR signaling by silencing both Nck isoforms, Nck1 and Nck2. In the absence of Nck, TCR phosphorylation, ZAP70 recruitment, and ZAP70 phosphorylation was impaired. Mechanistically, this is explained by loss of Lck recruitment to the stimulated TCR in cells lacking Nck. Hence, our data uncover a previously unknown cooperative interaction between Lck and Nck to promote optimal TCR signaling.https://www.mdpi.com/2073-4409/10/4/834TCRconformationLckNckRK motif |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Frederike A. Hartl Jatuporn Ngoenkam Esmeralda Beck-Garcia Liz Cerqueira Piyamaporn Wipa Pussadee Paensuwan Prapat Suriyaphol Pankaj Mishra Burkhart Schraven Stefan Günther Sutatip Pongcharoen Wolfgang W. A. Schamel Susana Minguet |
spellingShingle |
Frederike A. Hartl Jatuporn Ngoenkam Esmeralda Beck-Garcia Liz Cerqueira Piyamaporn Wipa Pussadee Paensuwan Prapat Suriyaphol Pankaj Mishra Burkhart Schraven Stefan Günther Sutatip Pongcharoen Wolfgang W. A. Schamel Susana Minguet Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling Cells TCR conformation Lck Nck RK motif |
author_facet |
Frederike A. Hartl Jatuporn Ngoenkam Esmeralda Beck-Garcia Liz Cerqueira Piyamaporn Wipa Pussadee Paensuwan Prapat Suriyaphol Pankaj Mishra Burkhart Schraven Stefan Günther Sutatip Pongcharoen Wolfgang W. A. Schamel Susana Minguet |
author_sort |
Frederike A. Hartl |
title |
Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling |
title_short |
Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling |
title_full |
Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling |
title_fullStr |
Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling |
title_full_unstemmed |
Cooperative Interaction of Nck and Lck Orchestrates Optimal TCR Signaling |
title_sort |
cooperative interaction of nck and lck orchestrates optimal tcr signaling |
publisher |
MDPI AG |
series |
Cells |
issn |
2073-4409 |
publishDate |
2021-04-01 |
description |
The T cell antigen receptor (TCR) is expressed on T cells, which orchestrate adaptive immune responses. It is composed of the ligand-binding clonotypic TCRαβ heterodimer and the non-covalently bound invariant signal-transducing CD3 complex. Among the CD3 subunits, the CD3ε cytoplasmic tail contains binding motifs for the Src family kinase, Lck, and the adaptor protein, Nck. Lck binds to a receptor kinase (RK) motif and Nck binds to a proline-rich sequence (PRS). Both motifs only become accessible upon ligand binding to the TCR and facilitate the recruitment of Lck and Nck independently of phosphorylation of the TCR. Mutations in each of these motifs cause defects in TCR signaling and T cell activation. Here, we investigated the role of Nck in proximal TCR signaling by silencing both Nck isoforms, Nck1 and Nck2. In the absence of Nck, TCR phosphorylation, ZAP70 recruitment, and ZAP70 phosphorylation was impaired. Mechanistically, this is explained by loss of Lck recruitment to the stimulated TCR in cells lacking Nck. Hence, our data uncover a previously unknown cooperative interaction between Lck and Nck to promote optimal TCR signaling. |
topic |
TCR conformation Lck Nck RK motif |
url |
https://www.mdpi.com/2073-4409/10/4/834 |
work_keys_str_mv |
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