Contrasting roles of DAP10 and KARAP/DAP12 signaling adaptors in activation of the RBL‐2H3 leukemic mast cell line

Abstract A common feature of hematopoietic activating immunoreceptors resides in their association at the cell surface with transmembrane signaling adaptors. Several adaptors, such as the CD3 molecules, FcRγ and KARAP/DAP12, harbor intracytoplasmic immunoreceptor tyrosine‐based activation motifs (ITAM) that activate Syk‐family protein tyrosine kinases. In contrast, another transmembrane adaptor, DAP10, bears a YxxM motif that delivers signals by activation of lipid kinase pathways. We show here that the human signal‐regulatory protein SIRPβ1 can associate with both DAP10 and KARAP/DAP12 in a model of RBL‐2H3 cell transfectants. In association with KARAP/DAP12, SIRPβ1 complexes are capable of inducing serotonin release and tumor necrosis factor (TNF) secretion. By contrast,in the absence of KARAP/DAP12, engagement of SIRPβ1:DAP10 complexes does not lead to detectable serotonin release or TNF secretion by RBL‐2H3 transfectants. However, triggering of SIRPβ1:DAP10 complexes co‐stimulates RBL‐2H3 effector function induced by sub‐optimal stimulation of the endogenous FcϵRI complex. Therefore, we report here a cellular model in which the association of a cell surface receptor with various signaling adaptors dictates the co‐stimulatory or the direct stimulatory properties of the complex.