Cutting edge: Dok-1 and Dok-2 adaptor molecules are regulated by phosphatidylinositol 5-phosphate production in T cells.
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.
Guittard
Geoffrey
G
Institut National de la Santé et de la Recherche Médicale, Centre de Recherche en Cancérologie de Marseille, France.
Gérard
Audrey
A
Dupuis-Coronas
Sophie
S
Tronchère
Hélène
H
Mortier
Eva
E
Favre
Cédric
C
Olive
Daniel
D
Zimmermann
Pascale
P
Payrastre
Bernard
B
Nunès
Jacques A
JA
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis* / Q000276:immunology; D010750:Phosphoproteins / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation; D016601:RNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C115089:DOK2 protein, human; D018129:Phosphatidylinositol Phosphates; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; C113567:phosphatidylinositol 5-phosphate