NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following Kit activation and Fc RI aggregation
Aggregation of high-affinity receptors for immunoglobulin E (FcRI) on the surface of mast cells results in degranulation, a response that is potentiated by binding of stem cell factor (SCF) to its receptor Kit. We observed that one of the major initial signaling events associated with FcRI- mediated activation of human mast cells (HuMCs) is the rapid tyrosine phosphory- lation of a protein of 25 to 30 kDa. The phosphorylation of this protein was also observed in response to SCF. This pro- tein was identified as non-T-cell activa- tion linker (NTAL), an adaptor molecule similar to linker for activated T cells (LAT). Unlike the FcRI response, SCF induced NTAL phosphorylation in the absence of detectable LAT phosphorylation. When SCF and antigen were added concur- rently, there was a marked synergistic effect on NTAL phosphorylation, how- ever, SCF did not enhance the phosphor- ylation of LAT induced by FcRI aggrega- tion. FcRI- and SCF-mediated NTAL phosphorylation appear to be differen- tially regulated by Src kinases and/or Kit kinase, respectively. Diminution of NTAL expression by silencing RNA oligonucleo- tides in HuMCs resulted in a reduction of both Kit- and FcRI-mediated degranula- tion. NTAL, thus, appears to be an impor- tant link between the signaling pathways that are initiated by these receptors, cul- minating in mast cell degranulation. (Blood. 2004;104:207-214)