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p62^dok Negatively Regulates CD2 Signaling in Jurkat Cells¹

Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval QC, Canada

p62^dok belongs to a newly identified family of adaptor proteins. In T cells, the two members that are predominantly expressed, p56^dok and p62^dok, are tyrosine phosphorylated upon CD2 or CD28 stimulation, but not upon CD3 ligation. Little is known about the biological role of Dok proteins in T cells. In this study, to evaluate the importance of p62^dok in T cell function, we generated Jurkat clones overexpressing p62^dok. Our results demonstrate that overexpression of p62^dok in Jurkat cells has a dramatic negative effect on CD2-mediated signaling. The p62^dok-mediated inhibition affects several biochemical events initiated by CD2 ligation, such as the increase of intracellular Ca²⁺, phospholipase C1 activation, and extracellular signal-regulated kinase 1/2 activation. Importantly, these cellular events are not affected in the signaling cascade induced by engagement of the CD3/TCR complex. However, both CD3- and CD2-induced NF-AT activation and IL-2 secretion are impaired in p62^dok-overexpressing cells. In addition, we show that CD2 but not CD3 stimulation induces p62^dok and Ras GTPase-activating protein recruitment to the plasma membrane. These results suggest that p62^dok plays a negative role at multiple steps in the CD2 signaling pathway. We propose that p62^dok may represent an important negative regulator in the modulation of the response mediated by the TCR.

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