The FcepsilonRIbeta immunoreceptor tyrosine-based activation motif exerts inhibitory control on MAPK and IkappaB kinase phosphorylation and mast cell cytokine production.
The high affinity IgE Fc receptor (FcepsilonRI) beta chain functions as a signal amplifier and has been linked to atopy, asthma, and allergy. Herein, we report on a previously unrecognized negative regulatory role for the nonconventional beta chain immunoreceptor tyrosine-based activation motif that contains three tyrosine residues (YX5YX3Y). Degranulation and leukotriene production was found to be impaired in cells expressing the mutated FcepsilonRIbeta immunoreceptor tyrosine-based activation motifs FYY, YYF, FYF, and FFF. In contrast, cytokine synthesis and secretion were enhanced in the YFY and FFF mutants. FcepsilonRI phosphorylation and Lyn kinase co-immunoprecipitation was intact in the YFY mutant but was lost in the FYF and FFF mutants. The phosphorylation of Syk, LAT, phospholipase gamma1/2, and Srchomology 2 domain-containing protein phosphatase 2 was intact, whereas the phosphorylation of SHIP-1 was significantly reduced in the YFY mutant cells. The FYF and FFF mutants were defective in phosphorylating all of these molecules. In contrast, the phosphorylation of ERK, p38 MAPK, IkappaB kinase beta (IKKbeta), and nuclear NFkappaB activity was enhanced in the YFY and FFF mutants. These findings show that the FcepsilonRIbeta functions to both selectively amplify (degranulation and leukotriene secretion) and dampen (lymphokine) mast cell effector responses.
Furumoto
Yasuko
Y
Molecular Inflammation Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nunomura
Satoshi
S
Terada
Tomoyoshi
T
Rivera
Juan
J
Ra
Chisei
C
D020816:Amino Acid Motifs; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002118:Calcium / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015151:Immunoblotting; D007073:Immunoglobulin E / Q000737:chemistry; D047468:Immunoprecipitation; D017997:Leukotriene C4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D051966:Phospholipase C gamma; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D017455:Receptors, IgE / Q000737:chemistry* / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014161:Transduction, Genetic; D010738:Type C Phospholipases / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D017455:Receptors, IgE; D017997:Leukotriene C4; D007073:Immunoglobulin E; D014443:Tyrosine; D048051:p38 Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D001619:beta-N-Acetylhexosaminidases; D002118:Calcium