Dok-4 is a novel negative regulator of T cell activation

Dok-4 (downstream of tyrosine kinase-4) is a recently identified member of the Dok family of adaptor proteins, which are characterized by an amino-terminal pleckstrin homology domain, a phosphotyrosine-binding domain, and a carboxyl-terminal region containing several tyrosines and poly-proline-rich...

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Autores principales:	Gérard, A., Ghiotto, M., Fos, C., Guittard, G., Compagno, D., Galy, A., Lemay, S., Olive, D., Nunès, J.A.
Formato:	JOUR
Materias:	downstream of tyrosine kinase 4 interleukin 2 mitogen activated protein kinase pleckstrin Rap1 protein regulator protein RNA T lymphocyte receptor unclassified drug DOK4 protein, human lymphocyte antigen receptor phosphotyrosine signal peptide article controlled study cytoplasm human human cell immunological synapse loss of function mutation lymphocyte proliferation microtubule polarization priority journal promoter region protein domain protein localization protein phosphorylation RNA interference T lymphocyte activation wild type antigen presenting cell cell communication cell line chemistry gene expression regulation genetics immunology lymphocyte activation metabolism microtubule organizing center protein motif signal transduction T lymphocyte Amino Acid Motifs Antigen-Presenting Cells Cell Communication Cell Line Gene Expression Regulation Humans Intracellular Signaling Peptides and Proteins Lymphocyte Activation Microtubule-Organizing Center Phosphotyrosine Promoter Regions, Genetic Receptors, Antigen, T-Cell Signal Transduction T-Lymphocytes
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00221767_v182_n12_p7681_Gerard
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_00221767_v182_n12_p7681_Gerard
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spelling	todo:paper_00221767_v182_n12_p7681_Gerard2023-10-03T14:27:56Z Dok-4 is a novel negative regulator of T cell activation Gérard, A. Ghiotto, M. Fos, C. Guittard, G. Compagno, D. Galy, A. Lemay, S. Olive, D. Nunès, J.A. downstream of tyrosine kinase 4 interleukin 2 mitogen activated protein kinase pleckstrin Rap1 protein regulator protein RNA T lymphocyte receptor unclassified drug DOK4 protein, human lymphocyte antigen receptor phosphotyrosine signal peptide article controlled study cytoplasm human human cell immunological synapse loss of function mutation lymphocyte proliferation microtubule polarization priority journal promoter region protein domain protein localization protein phosphorylation RNA interference T lymphocyte activation wild type antigen presenting cell cell communication cell line chemistry gene expression regulation genetics immunology lymphocyte activation metabolism microtubule organizing center protein motif signal transduction T lymphocyte Amino Acid Motifs Antigen-Presenting Cells Cell Communication Cell Line Gene Expression Regulation Humans Intracellular Signaling Peptides and Proteins Lymphocyte Activation Microtubule-Organizing Center Phosphotyrosine Promoter Regions, Genetic Receptors, Antigen, T-Cell Signal Transduction T-Lymphocytes Dok-4 (downstream of tyrosine kinase-4) is a recently identified member of the Dok family of adaptor proteins, which are characterized by an amino-terminal pleckstrin homology domain, a phosphotyrosine-binding domain, and a carboxyl-terminal region containing several tyrosines and poly-proline-rich motifs. Two members of the Dok family, Dok-1 and Dok-2, have already been described as negative regulators in T cells. However, the function of Dok-4, which is also expressed in T cells, remains unknown. In this study, we report that Dok-4 is phosphorylated after TCR engagement and shuttled within the cytoplasm of T cells before being recruited to the polarized microtubule organizing center after the formation of the immunological synapse. Loss-of-function experiments using RNA interference constructs show that Dok-4 is a negative regulator of ERK phosphorylation, IL-2 promoter activity, and T cell proliferation. Exogenous expression of wild-type Dok-4 induces a significant activation of Rap1, which is involved in the regulation of ERK. The pleckstrin homology domain of Dok-4 is required both for its cytoplasmic shuttling and relocalization as well as for its inhibitory properties on T cell activation. Thus, Dok-4 represents a novel negative regulator of T cells. Copyright © 2009 by The American Association of Immunologists, Inc. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00221767_v182_n12_p7681_Gerard
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	downstream of tyrosine kinase 4 interleukin 2 mitogen activated protein kinase pleckstrin Rap1 protein regulator protein RNA T lymphocyte receptor unclassified drug DOK4 protein, human lymphocyte antigen receptor phosphotyrosine signal peptide article controlled study cytoplasm human human cell immunological synapse loss of function mutation lymphocyte proliferation microtubule polarization priority journal promoter region protein domain protein localization protein phosphorylation RNA interference T lymphocyte activation wild type antigen presenting cell cell communication cell line chemistry gene expression regulation genetics immunology lymphocyte activation metabolism microtubule organizing center protein motif signal transduction T lymphocyte Amino Acid Motifs Antigen-Presenting Cells Cell Communication Cell Line Gene Expression Regulation Humans Intracellular Signaling Peptides and Proteins Lymphocyte Activation Microtubule-Organizing Center Phosphotyrosine Promoter Regions, Genetic Receptors, Antigen, T-Cell Signal Transduction T-Lymphocytes
spellingShingle	downstream of tyrosine kinase 4 interleukin 2 mitogen activated protein kinase pleckstrin Rap1 protein regulator protein RNA T lymphocyte receptor unclassified drug DOK4 protein, human lymphocyte antigen receptor phosphotyrosine signal peptide article controlled study cytoplasm human human cell immunological synapse loss of function mutation lymphocyte proliferation microtubule polarization priority journal promoter region protein domain protein localization protein phosphorylation RNA interference T lymphocyte activation wild type antigen presenting cell cell communication cell line chemistry gene expression regulation genetics immunology lymphocyte activation metabolism microtubule organizing center protein motif signal transduction T lymphocyte Amino Acid Motifs Antigen-Presenting Cells Cell Communication Cell Line Gene Expression Regulation Humans Intracellular Signaling Peptides and Proteins Lymphocyte Activation Microtubule-Organizing Center Phosphotyrosine Promoter Regions, Genetic Receptors, Antigen, T-Cell Signal Transduction T-Lymphocytes Gérard, A. Ghiotto, M. Fos, C. Guittard, G. Compagno, D. Galy, A. Lemay, S. Olive, D. Nunès, J.A. Dok-4 is a novel negative regulator of T cell activation
topic_facet	downstream of tyrosine kinase 4 interleukin 2 mitogen activated protein kinase pleckstrin Rap1 protein regulator protein RNA T lymphocyte receptor unclassified drug DOK4 protein, human lymphocyte antigen receptor phosphotyrosine signal peptide article controlled study cytoplasm human human cell immunological synapse loss of function mutation lymphocyte proliferation microtubule polarization priority journal promoter region protein domain protein localization protein phosphorylation RNA interference T lymphocyte activation wild type antigen presenting cell cell communication cell line chemistry gene expression regulation genetics immunology lymphocyte activation metabolism microtubule organizing center protein motif signal transduction T lymphocyte Amino Acid Motifs Antigen-Presenting Cells Cell Communication Cell Line Gene Expression Regulation Humans Intracellular Signaling Peptides and Proteins Lymphocyte Activation Microtubule-Organizing Center Phosphotyrosine Promoter Regions, Genetic Receptors, Antigen, T-Cell Signal Transduction T-Lymphocytes
description	Dok-4 (downstream of tyrosine kinase-4) is a recently identified member of the Dok family of adaptor proteins, which are characterized by an amino-terminal pleckstrin homology domain, a phosphotyrosine-binding domain, and a carboxyl-terminal region containing several tyrosines and poly-proline-rich motifs. Two members of the Dok family, Dok-1 and Dok-2, have already been described as negative regulators in T cells. However, the function of Dok-4, which is also expressed in T cells, remains unknown. In this study, we report that Dok-4 is phosphorylated after TCR engagement and shuttled within the cytoplasm of T cells before being recruited to the polarized microtubule organizing center after the formation of the immunological synapse. Loss-of-function experiments using RNA interference constructs show that Dok-4 is a negative regulator of ERK phosphorylation, IL-2 promoter activity, and T cell proliferation. Exogenous expression of wild-type Dok-4 induces a significant activation of Rap1, which is involved in the regulation of ERK. The pleckstrin homology domain of Dok-4 is required both for its cytoplasmic shuttling and relocalization as well as for its inhibitory properties on T cell activation. Thus, Dok-4 represents a novel negative regulator of T cells. Copyright © 2009 by The American Association of Immunologists, Inc.
format	JOUR
author	Gérard, A. Ghiotto, M. Fos, C. Guittard, G. Compagno, D. Galy, A. Lemay, S. Olive, D. Nunès, J.A.
author_facet	Gérard, A. Ghiotto, M. Fos, C. Guittard, G. Compagno, D. Galy, A. Lemay, S. Olive, D. Nunès, J.A.
author_sort	Gérard, A.
title	Dok-4 is a novel negative regulator of T cell activation
title_short	Dok-4 is a novel negative regulator of T cell activation
title_full	Dok-4 is a novel negative regulator of T cell activation
title_fullStr	Dok-4 is a novel negative regulator of T cell activation
title_full_unstemmed	Dok-4 is a novel negative regulator of T cell activation
title_sort	dok-4 is a novel negative regulator of t cell activation
url	http://hdl.handle.net/20.500.12110/paper_00221767_v182_n12_p7681_Gerard
work_keys_str_mv	AT gerarda dok4isanovelnegativeregulatoroftcellactivation AT ghiottom dok4isanovelnegativeregulatoroftcellactivation AT fosc dok4isanovelnegativeregulatoroftcellactivation AT guittardg dok4isanovelnegativeregulatoroftcellactivation AT compagnod dok4isanovelnegativeregulatoroftcellactivation AT galya dok4isanovelnegativeregulatoroftcellactivation AT lemays dok4isanovelnegativeregulatoroftcellactivation AT olived dok4isanovelnegativeregulatoroftcellactivation AT nunesja dok4isanovelnegativeregulatoroftcellactivation
_version_	1782023918438055936

Dok-4 is a novel negative regulator of T cell activation

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