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J. Biol. Chem., Vol. 276, Issue 46, 42893-42900, November 16, 2001

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IgE Receptor Type I-dependent Regulation of a Rab3D-associated Kinase
A POSSIBLE LINK IN THE CALCIUM-DEPENDENT ASSEMBLY OF SNARE COMPLEXES^*

Isabel Pombo^§, Sophie Martin-Verdeaux, Bruno Iannascoli, Joëlle Le Mao, Ludovic Deriano, Juan Rivera^¶, and Ulrich Blank

From the  Unité d'Immuno-Allergie, Institut Pasteur, 75724 Paris Cedex 15, France and the ^¶ Molecular Inflammation Section, NIAMS, National Institutes of Health, Bethesda, Maryland 20892

Following activation through high affinity IgE receptors (FcRI), mast cells release, within a few minutes, their granule content of inflammatory and allergic mediators. FcRI-induced degranulation is a SNARE (soluble N-ethylmaleimide attachment protein receptors)-dependent fusion process. It is regulated by Rab3D, a subfamily member of Rab GTPases. Evidence exists showing that Rab3 action is calcium-regulated although the molecular mechanisms remain unclear. To obtain an understanding of Rab3D function we have searched for Rab3D-associated effectors that respond to allergic triggering through FcRI. Using the RBL-2H3 mast cell line we detected a Ser/Thr kinase activity, termed here Rak3D (from Rab3D-associated kinase), because it was specifically co-immunoprecipitated with anti-Rab3D antibody. Rak3D activity, as measured by its auto- or transphosphorylation, was maximal in resting cells and decreased upon stimulation. The down-regulation of the observed activity was blocked with EGTA, but not with other degranulation inhibitors, suggesting that its activity functions downstream of calcium influx. We found that Rak3D phosphorylates the NH₂-terminal regulatory domain of the t-SNARE syntaxin 4, but not syntaxin 2 or 3. The phosphorylation of syntaxin 4 decreased its binding to its partner SNAP23. Thus, we propose a novel phosphorylation-dependent mechanism by which Rab3D controls SNARE assembly in a calcium-dependent manner.

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