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

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.
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Submitted on : Tuesday, December 15, 2009 - 3:40:12 PM
Last modification on : Wednesday, September 16, 2020 - 5:06:39 PM
Long-term archiving on: : Thursday, June 10, 2010 - 6:22:18 PM

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Audrey Gérard, Marguerite Ghiotto, Camille Fos, Geoffrey Guittard, Daniel Compagno, et al.. Dok-4 is a novel negative regulator of T cell activation.: Dok-4 and T cell activation. Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2009, 182 (12), pp.7681-9. ⟨10.4049/jimmunol.0802203⟩. ⟨inserm-00374930⟩

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