Cutting Edge: Dok-1 and Dok-2 Adaptor Molecules Are Regulated by Phosphatidylinositol 5-Phosphate Production in T Cells

Institut National de la Santé et de la Recherche Médicale, Centre de Recherche en Cancérologie de Marseille, France.
The Journal of Immunology (Impact Factor: 4.92). 05/2009; 182(7):3974-8. DOI: 10.4049/jimmunol.0804172
Source: PubMed


Downstream of tyrosine kinase (Dok) proteins Dok-1 and Dok-2 are involved in T cell homeostasis maintenance. Dok protein tyrosine phosphorylation plays a key role in establishing negative feedback loops of T cell signaling. These structurally related adapter molecules contain a pleckstrin homology (PH) domain generally acting as a lipid/protein-interacting module. We show that the presence of this PH domain is necessary for the tyrosine phosphorylation of Dok proteins and their negative functions in T cells. We find that Dok-1/Dok-2 PH domains bind in vitro to the rare phosphoinositide species, phosphatidylinositol 5-phosphate (PtdIns5P). Dok tyrosine phosphorylation correlates with PtdIns5P production in T cells upon TCR triggering. Furthermore, we demonstrate that PtdIns5P increase regulates Dok tyrosine phosphorylation in vivo. Together, our data identify a novel lipid mediator in T cell signaling and suggest that PH-PtdIns5P interactions regulate T cell responses.

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    • "Upon T cell stimulation, these PH domain-containing proteins are recruited to (or are in the vicinity of) the plasma membrane (Boulay et al., 2005; Gerard et al., 2009). Dok-1 and Dok-2 PH domains were shown to bind PI5P and PI4P in SPR analysis (Guittard et al., 2009). But using different enzymatic approaches, PI5P appeared to be essential for Dok proteins tyrosine phosphorylation. "
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    ABSTRACT: Phosphoinositides are critical regulators in cell biology. Phosphatidylinositol 4,5-bisphosphate, also known as PI(4,5)P2 or PIP2, was the first variety of phosphoinositide to enter in the T cell signaling scene. Phosphatidylinositol bis-phosphates are the substrates for different types of enzymes such as phospholipases C (β and γ isoforms) and phosphoinositide 3-kinases (PI3K class IA and IB) that are largely involved in signal transduction. However until recently, only a few studies highlighted phosphatidylinositol monophosphates as signaling molecules. This was mostly due to the difficulty of detection of some of these phosphoinositides, such as phosphatidylinositol 5-phosphate, also known as PI5P. Some compelling evidence argues for a role of PI5P in cell signaling and/or cell trafficking. Recently, we reported the detection of a PI5P increase upon TCR triggering. Here, we describe the current knowledge of the role of PI5P in T cell signaling. The future challenges that will be important to achieve in order to fully characterize the role of PI5P in T cell biology, will be discussed.
    Frontiers in Immunology 04/2013; 4:80. DOI:10.3389/fimmu.2013.00080
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    • "IpgD-mediated hydrolysis of PIP 2 has been shown to occur in epithelial cells (Niebuhr et al., 2002) and in Jurkat cells (Guittard et al., 2009). Since most of the PIP 2 pool is located at the plasma membrane, we expected that the IpgD-mediated PIP 2 hydrolysis in T cells would affect the plasma membrane PIP 2 pool. "
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    • "Recently, we observed that PtdIns5P is produced in T cells upon TCR triggering. This production leads to Dok-1 and Dok-2 tyrosine phosphorylation and subsequent T cell signaling negative regulation, suggesting that PtdIns5P is a second messenger downstream of TCR stimulation [11]. "
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    ABSTRACT: Phosphatidylinositol 5-phosphate (PtdIns5P) is emerging as a potential lipid messenger involved in several cell types, from plants to mammals. Expression of IpgD, a PtdIns(4,5)P(2) 4-phosphatase induces Src kinase and Akt, but not ERK activation and enhances interleukin II promoter activity in T-cells. Expression of a new PtdIns5P interacting domain blocks IpgD-induced T-cell activation and selective signaling molecules downstream of TCR triggering. Altogether, these data suggest that PtdIns5P may play a sensor function in setting the threshold of T-cell activation and contributing to maintain T-cell homeostasis.
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