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 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.
Gérard
Audrey
A
Unité 891, Institut National de la Santé et de la Recherche Médicale, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
Ghiotto
Marguerite
M
Fos
Camille
C
Guittard
Geoffrey
G
Compagno
Daniel
D
Galy
Anne
A
Lemay
Serge
S
Olive
Daniel
D
Nunès
Jacques A
JA
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D022101:Microtubule-Organizing Center / Q000276:immunology / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C486625:DOK4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine