Fc receptor signal initiation mechanisms at lipid rafts

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Antigen receptors, consists of T and B cell receptors and those for Fc portion of Immunoglobulines (Fc receptors for Igs) play central roles in the initial step of immune regulation. It was assumed that receptor engagement is sensed and converted by Src family kinases (SFKs) to cell-inner events. To elucidate the SFK specificity, we introduced novel strategies and established their requirement and specificity in Fc, and c-Kit and Integrin receptors. Notably, SFKs responsible for Fc receptor signaling are all modified with palmitic acid, and they reside in a membrane domain referred to as 'lipid rafts'. We have also shown that special lipid raft-coalescence is an upstream event to SFK activation. It could be assumed that raft-coalescence provides a field for SFKs transactivate on another. We are searching for the molecule(s) responsible for Fc receptor-mediated lipid raft assembly. Next we have cloned two novel molecules interacting with a SFK, Lyn. One possess RING domain and another is a huge adaptor protein possessing putative Grb2 and PI3K binding sites and GAP domain. Third, we are investigating functional differences in polymorphic forms of negatige regulatory Fc receptor for IgG (FcγRIIb), one of which (rare allele) is genetically linked to systemic lupus erythematodes.