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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.

Original publication

DOI

10.4049/jimmunol.0802203

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

06/2009

Volume

182

Pages

7681 - 7689

Addresses

Unité 891, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche en Cancérologie de Marseille, Marseille, France.

Keywords

Antigen-Presenting Cells, T-Lymphocytes, Cell Line, Microtubule-Organizing Center, Humans, Phosphotyrosine, Intracellular Signaling Peptides and Proteins, Receptors, Antigen, T-Cell, Lymphocyte Activation, Cell Communication, Signal Transduction, Gene Expression Regulation, Amino Acid Motifs, Promoter Regions, Genetic