NTAL phosphorylation is a pivotal link between the signaling cascades leading to human mast cell degranulation following Kit activation and Fc epsilon RI aggregation.
Aggregation of high-affinity receptors for immunoglobulin E (Fc epsilon RI) 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 Fc epsilon RI-mediated activation of human mast cells (HuMCs) is the rapid tyrosine phosphorylation of a protein of 25 to 30 kDa. The phosphorylation of this protein was also observed in response to SCF. This protein was identified as non-T-cell activation linker (NTAL), an adaptor molecule similar to linker for activated T cells (LAT). Unlike the Fc epsilon RI response, SCF induced NTAL phosphorylation in the absence of detectable LAT phosphorylation. When SCF and antigen were added concurrently, there was a marked synergistic effect on NTAL phosphorylation, however, SCF did not enhance the phosphorylation of LAT induced by Fc epsilon RI aggregation. Fc epsilon RI- and SCF-mediated NTAL phosphorylation appear to be differentially regulated by Src kinases and/or Kit kinase, respectively. Diminution of NTAL expression by silencing RNA oligonucleotides in HuMCs resulted in a reduction of both Kit- and Fc epsilon RI-mediated degranulation. NTAL, thus, appears to be an important link between the signaling pathways that are initiated by these receptors, culminating in mast cell degranulation.
Tkaczyk
Christine
C
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Horejsi
Vaclav
V
Iwaki
Shoko
S
Draber
Petr
P
Samelson
Lawrence E
LE
Satterthwaite
Anne B
AB
Nahm
Dong-Ho
DH
Metcalfe
Dean D
DD
Gilfillan
Alasdair M
AM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000941:Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000096:biosynthesis; D015550:Cell Degranulation / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008407:Mast Cells / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D010750:Phosphoproteins / Q000096:biosynthesis; D010766:Phosphorylation; D011506:Proteins / Q000276:immunology / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000276:immunology / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
C412373:AG 1879; D048868:Adaptor Proteins, Signal Transducing; D000941:Antigens; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; C110810:LAT protein, human; C419196:LAT2 protein, human; C488163:LAT2 protein, mouse; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D011506:Proteins; D011743:Pyrimidines; D034741:RNA, Small Interfering; D017455:Receptors, IgE; D019089:Stem Cell Factor; D013267:Stilbenes; D014443:Tyrosine; C041525:3,3',4,5'-tetrahydroxystilbene; D019009:Proto-Oncogene Proteins c-kit; D019061:src-Family Kinases