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Article: Detection of Intracellular Reduced (Catalytically Active) SHP-1 and Analyses of Catalytically Inactive SHP-1 after Oxidation by Pervanadate or H

Choi, Seeyoung / Love, Paul E

2018 Volume 8, Issue 1

Abstract: Oxidative inactivation of cysteine-dependent Protein Tyrosine Phosphatases (PTPs) by cellular reactive oxygen species (ROS) plays a critical role in regulating signal transduction in multiple cell types. The phosphatase activity of most PTPs depends upon ...

Abstract	Oxidative inactivation of cysteine-dependent Protein Tyrosine Phosphatases (PTPs) by cellular reactive oxygen species (ROS) plays a critical role in regulating signal transduction in multiple cell types. The phosphatase activity of most PTPs depends upon a 'signature' cysteine residue within the catalytic domain that is maintained in the de-protonated state at physiological pH rendering it susceptible to ROS-mediated oxidation. Direct and indirect techniques for detection of PTP oxidation have been developed (Karisch and Neel, 2013). To detect catalytically active PTPs, cell lysates are treated with iodoacetyl-polyethylene glycol-biotin (IAP-biotin), which irreversibly binds to reduced (S
Language	English
Publishing date	2018-03-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.2684
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Article ; Online: Publisher Correction: CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides.

Gaud, Guillaume / Achar, Sooraj / Bourassa, François X P / Davies, John / Hatzihristidis, Teri / Choi, Seeyoung / Kondo, Taisuke / Gossa, Selamawit / Lee, Jan / Juneau, Paul / Taylor, Naomi / Hinrichs, Christian S / McGavern, Dorian B / François, Paul / Altan-Bonnet, Grégoire / Love, Paul E

Nature immunology

2023 Volume 25, Issue 3, Page(s) 579

Language	English
Publishing date	2023-12-03
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01725-5
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Zs.A 5294: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 42: Show issues

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Article ; Online: THEMIS increases TCR signaling in CD4

Choi, Seeyoung / Lee, Jan / Hatzihristidis, Teri / Gaud, Guillaume / Dutta, Avik / Arya, Awadhesh / Clubb, Lauren M / Stamos, Daniel B / Markovics, Adrienn / Mikecz, Katalin / Love, Paul E

Science signaling

2023 Volume 16, Issue 784, Page(s) eade1274

Abstract: The T cell lineage-restricted protein THEMIS plays a critical role in T cell development at the positive selection stage. In the SHP1 activation model, THEMIS is proposed to enhance the activity of the tyrosine phosphatase SHP1 (encoded ... ...

Abstract	The T cell lineage-restricted protein THEMIS plays a critical role in T cell development at the positive selection stage. In the SHP1 activation model, THEMIS is proposed to enhance the activity of the tyrosine phosphatase SHP1 (encoded by
MeSH term(s)	CD8-Positive T-Lymphocytes ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics ; Thymocytes ; Animals ; Intercellular Signaling Peptides and Proteins/genetics
Chemical Substances	Protein Tyrosine Phosphatase, Non-Receptor Type 6 (EC 3.1.3.48) ; Intercellular Signaling Peptides and Proteins
Language	English
Publishing date	2023-05-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.ade1274
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Article ; Online: GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1.

Choi, Seeyoung / Hatzihristidis, Teri / Gaud, Guillaume / Dutta, Avik / Lee, Jan / Arya, Awadhesh / Clubb, Lauren M / Stamos, Daniel B / Markovics, Adrienn / Mikecz, Katalin / Love, Paul

The Journal of experimental medicine

2023 Volume 220, Issue 7

Abstract: The T-lineage restricted protein THEMIS has been shown to play a critical role in T cell development. THEMIS, via its distinctive CABIT domains, inhibits the catalytic activity of the tyrosine phosphatase SHP1 (PTPN6). SHP1 and THEMIS bind to the ... ...

Abstract	The T-lineage restricted protein THEMIS has been shown to play a critical role in T cell development. THEMIS, via its distinctive CABIT domains, inhibits the catalytic activity of the tyrosine phosphatase SHP1 (PTPN6). SHP1 and THEMIS bind to the ubiquitous cytosolic adapter GRB2, and the purported formation of a tri-molecular THEMIS-GRB2-SHP1 complex facilitates inactivation of SHP1 by THEMIS. The importance of this function of GRB2 among its numerous documented activities is unclear as GRB2 binds to multiple proteins and participates in several signaling responses in thymocytes. Here, we show that similar to Themis-/- thymocytes, the primary molecular defect in GRB2-deficient thymocytes is increased catalytically active SHP1 and the developmental block in GRB2-deficient thymocytes is alleviated by deletion or inhibition of SHP1 and is exacerbated by SHP1 overexpression. Thus, the principal role of GRB2 during T cell development is to promote THEMIS-mediated inactivation of SHP1 thereby enhancing the sensitivity of TCR signaling in CD4+CD8+ thymocytes to low affinity positively selecting self-ligands.
MeSH term(s)	Cell Differentiation ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Signal Transduction ; Thymocytes/metabolism ; GRB2 Adaptor Protein/metabolism
Chemical Substances	Protein Tyrosine Phosphatase, Non-Receptor Type 6 (EC 3.1.3.48) ; Receptors, Antigen, T-Cell ; GRB2 Adaptor Protein
Language	English
Publishing date	2023-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20221649
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Ua VI Zs.107: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides.

Nature immunology

2023 Volume 24, Issue 12, Page(s) 2121–2134

Abstract: The T cell antigen receptor (TCR) contains ten immunoreceptor tyrosine-based activation motif (ITAM) signaling sequences distributed within six CD3 subunits; however, the reason for such structural complexity and multiplicity is unclear. Here we ... ...

Abstract	The T cell antigen receptor (TCR) contains ten immunoreceptor tyrosine-based activation motif (ITAM) signaling sequences distributed within six CD3 subunits; however, the reason for such structural complexity and multiplicity is unclear. Here we evaluated the effect of inactivating the three CD3ζ chain ITAMs on TCR signaling and T cell effector responses using a conditional 'switch' mouse model. Unexpectedly, we found that T cells expressing TCRs containing inactivated (non-signaling) CD3ζ ITAMs (6F-CD3ζ) exhibited reduced ability to discriminate between low- and high-affinity ligands, resulting in enhanced signaling and cytokine responses to low-affinity ligands because of a previously undetected inhibitory function of CD3ζ ITAMs. Also, 6F-CD3ζ TCRs were refractory to antagonism, as predicted by a new in silico adaptive kinetic proofreading model that revises the role of ITAM multiplicity in TCR signaling. Finally, T cells expressing 6F-CD3ζ displayed enhanced cytolytic activity against solid tumors expressing low-affinity ligands, identifying a new counterintuitive approach to TCR-mediated cancer immunotherapy.
MeSH term(s)	Animals ; Mice ; CD3 Complex ; Immunoreceptor Tyrosine-Based Activation Motif ; Ligands ; Peptides ; Receptors, Antigen, T-Cell ; T-Lymphocytes
Chemical Substances	CD3 Complex ; Ligands ; Peptides ; Receptors, Antigen, T-Cell ; CD3 antigen, zeta chain
Language	English
Publishing date	2023-11-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/s41590-023-01663-2
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Article ; Online: THEMIS: Two Models, Different Thresholds.

Choi, Seeyoung / Cornall, Richard / Lesourne, Renaud / Love, Paul E

Trends in immunology

2017 Volume 38, Issue 9, Page(s) 622–632

Abstract: THEMIS, a recently identified T-lineage-restricted protein, is the founding member of a large metazoan protein family. Gene inactivation studies have revealed a critical requirement for THEMIS during thymocyte positive selection, implicating THEMIS in ... ...

Abstract	THEMIS, a recently identified T-lineage-restricted protein, is the founding member of a large metazoan protein family. Gene inactivation studies have revealed a critical requirement for THEMIS during thymocyte positive selection, implicating THEMIS in signaling downstream of the T cell antigen receptor (TCR), but the mechanistic underpinnings of THEMIS function have remained elusive. A previous model posited that THEMIS prevents thymocytes from inappropriately crossing the positive/negative selection threshold by dampening TCR signaling. However, new data suggest an alternative model where THEMIS enhances TCR signaling enabling thymocytes to reach the threshold for positive selection, avoiding death by neglect. We review the data supporting each model and conclude that the preponderance of evidence favors an enhancing function for THEMIS in TCR signaling.
MeSH term(s)	Animals ; Cell Differentiation ; Cysteine/genetics ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Lymphocyte Activation ; Models, Immunological ; Protein Domains/genetics ; Receptors, Antigen, T-Cell/metabolism ; Signal Transduction ; T-Lymphocytes/physiology ; Thymocytes/physiology
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Receptors, Antigen, T-Cell ; thymocyte-expressed molecule involved in selection, human ; Cysteine (K848JZ4886)
Language	English
Publishing date	2017-07-08
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Intramural
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2017.06.006
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Zs.A 1601: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 2: Show issues

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Article ; Online: CD5 dynamically calibrates basal NF-κB signaling in T cells during thymic development and peripheral activation.

Matson, Courtney A / Choi, Seeyoung / Livak, Ferenc / Zhao, Bin / Mitra, Apratim / Love, Paul E / Singh, Nevil J

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 25, Page(s) 14342–14353

Abstract: Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface ...

Abstract	Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface glycoprotein CD5, are up-regulated in proportion to the strength of the self-peptide signal. Together these regulators dampen TCR-proximal signaling and help avoid any subsequent peripheral activation of T cells by self-peptides. Paradoxically, antigen-specific T cells initially expressing more CD5 (CD5
MeSH term(s)	Adoptive Transfer ; Animals ; Antigen Presentation/immunology ; CD5 Antigens/genetics ; CD5 Antigens/metabolism ; Cell Line, Tumor ; Cell Separation ; Cell Survival/immunology ; Female ; Flow Cytometry ; Gene Expression Regulation, Developmental/immunology ; Lipopolysaccharides/immunology ; Lymphocyte Activation ; Mice ; Mice, Knockout ; Models, Animal ; NF-KappaB Inhibitor alpha/metabolism ; Primary Cell Culture ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; Receptors, Antigen, T-Cell, alpha-beta/metabolism ; Signal Transduction/immunology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/transplantation ; Thymus Gland/cytology ; Thymus Gland/growth & development ; Thymus Gland/immunology ; Transcription Factor RelA/metabolism ; Up-Regulation
Chemical Substances	CD5 Antigens ; Cd5 protein, mouse ; Lipopolysaccharides ; Nfkbia protein, mouse ; Receptors, Antigen, T-Cell, alpha-beta ; Rela protein, mouse ; Transcription Factor RelA ; NF-KappaB Inhibitor alpha (139874-52-5) ; Protein Tyrosine Phosphatase, Non-Receptor Type 6 (EC 3.1.3.48) ; Ptpn6 protein, mouse (EC 3.1.3.48)
Language	English
Publishing date	2020-06-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1922525117
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Article ; Online: Erratum: THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1.

Choi, Seeyoung / Warzecha, Claude / Zvezdova, Ekaterina / Lee, Jan / Argenty, Jérémy / Lesourne, Renaud / Aravind, L / Love, Paul E

Nature immunology

2017 Volume 18, Issue 6, Page(s) 705

Language	English
Publishing date	2017-05-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2016987-5
ISSN	1529-2916 ; 1529-2908
ISSN (online)	1529-2916
ISSN	1529-2908
DOI	10.1038/ni0617-705c
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Article ; Online: Impairment of immunological synapse formation in adaptively tolerant T cells.

Choi, Seeyoung / Schwartz, Ronald H

Journal of immunology (Baltimore, Md. : 1950)

2011 Volume 187, Issue 2, Page(s) 805–816

Abstract: Adaptive tolerance is a hyporesponsive state in which lymphocyte Ag receptor signaling becomes desensitized after prolonged in vivo encounter with Ag. The molecular mechanisms underlying this hyporesponsive state in T cells are not fully understood, ... ...

Abstract	Adaptive tolerance is a hyporesponsive state in which lymphocyte Ag receptor signaling becomes desensitized after prolonged in vivo encounter with Ag. The molecular mechanisms underlying this hyporesponsive state in T cells are not fully understood, although a major signaling block has been shown to be present at the level of ZAP70 phosphorylation of linker for activation of T cells (LAT). In this study, we investigated the ability of adaptively tolerant mouse T cells to form conjugates with Ag-bearing APCs and to translocate signaling molecules into the interface between the T cells and APCs. Compared with naive or preactivated T cells, adaptively tolerant T cells showed no dramatic impairment in their formation of conjugates with APCs. In contrast, there was a large impairment in immunological synapse formation. Adaptively tolerant T cells were defective in their translocation of signaling molecules, such as ZAP70, LAT, and phospholipase C γ1, into the T cell-APC contact sites. Although Ag-induced activation of VAV1 was normal, VAV's recruitment into the synapse was also impaired. Interestingly, expressions of both IL-2-inducible T cell kinase and growth factor receptor-bound protein 2-related adaptor downstream of SHC were decreased by 60-80% in adaptively tolerant T cells. These decreases, in addition to the impairment in LAT phosphorylation by ZAP70, appear to be the major impediments to the phosphorylation of SLP76 (SRC homology 2 domain-containing leukocyte protein of 76 kDa) and the recruitment of VAV1, which are important for stable immunological synapse formation.
MeSH term(s)	Adaptive Immunity/genetics ; Adaptor Proteins, Signal Transducing/antagonists & inhibitors ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Antigen-Presenting Cells/immunology ; Antigen-Presenting Cells/metabolism ; Cell Line ; Clonal Anergy/genetics ; Down-Regulation/genetics ; Down-Regulation/immunology ; GRB2 Adaptor Protein/antagonists & inhibitors ; Immunological Synapses/genetics ; Membrane Proteins/antagonists & inhibitors ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred A ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Phosphorylation/immunology ; Protein Transport/immunology ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Protein-Tyrosine Kinases/biosynthesis ; Proto-Oncogene Proteins c-vav ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; GRB2 Adaptor Protein ; GRB2 protein, human ; LAT protein, human ; Membrane Proteins ; Proto-Oncogene Proteins c-vav ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; emt protein-tyrosine kinase (EC 2.7.10.2)
Language	English
Publishing date	2011-06-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1003314
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Article ; Online: SOCS3 is a suppressor of γc cytokine signaling and constrains generation of murine Foxp3

Luckey, Megan A / Kim, Tae-Hyoun / Prakhar, Praveen / Keller, Hilary R / Crossman, Assiatu / Choi, Seeyoung / Love, Paul E / Walsh, Scott T R / Park, Jung-Hyun

European journal of immunology

2020 Volume 50, Issue 7, Page(s) 986–999

Abstract: SOCS3 is a cytosolic inhibitor of cytokine signaling that suppresses the activation of cytokine receptor-associated JAK kinases. Mechanistically, SOCS3 is recruited to a site in the cytokine receptors known as the SOCS3-interaction motif, and then binds ... ...

Abstract	SOCS3 is a cytosolic inhibitor of cytokine signaling that suppresses the activation of cytokine receptor-associated JAK kinases. Mechanistically, SOCS3 is recruited to a site in the cytokine receptors known as the SOCS3-interaction motif, and then binds JAK molecules to inhibit their kinase activity. The SOCS3-interaction motif is found in receptors of the gp130 cytokine family but mostly absent from other cytokine receptors, including γc. Thus, SOCS3 has been considered a selective suppressor of gp130 family cytokines, but not γc cytokines. Considering that γc signaling induces SOCS3 expression in T cells, here we revisited the role of SOCS3 on γc signaling. Using SOCS3 transgenic mice, we found that increased abundance of SOCS3 not only suppressed signaling of the gp130 family cytokine IL-6, but also signaling of the γc family cytokine IL-7. Consequently, SOCS3 transgenic mice were impaired in IL-7-dependent T cell development in the thymus and the homeostasis of mature T cells in peripheral tissues. Moreover, enforced SOCS3 expression interfered with the generation of Foxp3
MeSH term(s)	Animals ; Cytokines/immunology ; Female ; Forkhead Transcription Factors/immunology ; Immunity, Cellular ; Male ; Mice ; Signal Transduction/immunology ; Suppressor of Cytokine Signaling 3 Protein/immunology ; T-Lymphocytes, Regulatory/cytology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Cytokines ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Socs3 protein, mouse ; Suppressor of Cytokine Signaling 3 Protein
Language	English
Publishing date	2020-03-19
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201948307
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