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RI Signaling and Altered Fyn and SHIP Activities in Lyn-Deficient Mast Cells1
* Department of Pathology and Cancer Research and Treatment Center, University of New Mexico School of Medicine, Albuquerque, NM 87131;
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada; and
Department of Laboratory Medicine, University of California, San Francisco, CA 94143
Studies in B cells from Lyn-deficient mice have identified Lyn as both a kinetic accelerator and negative regulator of signaling through the BCR. The signaling properties of bone marrow-derived mast cells from Lyn–/– mice (Lyn–/– BMMCs) have also been explored, but their signaling phenotype remains controversial. We confirm that Lyn–/– BMMCs release more 
-hexosaminidase than wild-type BMMCs following Fc
RI cross-linking and show that multiple mast cell responses to FcRI cross-linking (the phosphorylation of receptor subunits and other proteins, the activation of phospholipase C
isoforms, the mobilization of Ca2+, the synthesis of phosphatidylinositol 3,4,5-trisphosphate, the activation of the 
41 integrin, VLA-4) are slow to initiate in Lyn–/– BMMCs, but persist far longer than in wild-type cells. Mechanistic studies revealed increased basal as well as stimulated phosphorylation of the Src kinase, Fyn, in Lyn–/– BMMCs. Conversely, there was very little basal or stimulated tyrosine phosphorylation or activity of the inositol phosphatase, SHIP, in Lyn–/– BMMCs. We speculate that Fyn may substitute (inefficiently) for Lyn in signal initiation in Lyn–/– BMMCs. The loss of SHIP phosphorylation and activity very likely contributes to the increased levels of phosphatidylinositol 3,4,5-trisphosphate and the excess FcRI signaling in Lyn–/– BMMCs. The unexpected absence of the transient receptor potential channel, Trpc4, from Lyn–/– BMMCs may additionally contribute to their altered signaling properties.
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