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

J Immunol. 2009 Jun 15;182(12):7681-9. doi: 10.4049/jimmunol.0802203.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Motifs
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Cell Communication / immunology
  • Cell Line
  • Gene Expression Regulation
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lymphocyte Activation / immunology*
  • Microtubule-Organizing Center / immunology
  • Microtubule-Organizing Center / metabolism
  • Phosphotyrosine / metabolism
  • Promoter Regions, Genetic / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • DOK4 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Antigen, T-Cell
  • Phosphotyrosine