Positive and negative regulation of mast cell activation by Lyn via the FcepsilonRI.
Aggregation of the high affinity receptor for IgE (FcepsilonRI) induces activation of mast cells. In this study we show that upon low intensity stimulation of FcepsilonRI with monomeric IgE, IgE plus anti-IgE, or IgE plus low Ag, Lyn (a Src family kinase) positively regulates degranulation, cytokine production, and survival, whereas Lyn works as a negative regulator of high intensity stimulation with IgE plus high Ag. Low intensity stimulation suppressed Lyn kinase activity and its association with FcepsilonRI beta subunit, whereas high intensity stimulation enhanced Lyn activity and its association with FcepsilonRI beta. The latter induced much higher levels of FcepsilonRI beta phosphorylation and Syk activity than the former. Downstream positive signaling molecules, such as Akt and p38, were positively and negatively regulated by Lyn upon low and high intensity stimulations, respectively. In contrast, the negative regulators, SHIP and Src homology 2 domain-containing protein tyrosine phosphatase-1, interacted with FcepsilonRI beta, and their phosphorylation was controlled by Lyn. Therefore, we conclude that Lyn-mediated positive vs negative regulation depends on the intensity of the stimuli. Studies of mutant FcepsilonRI beta showed that FcepsilonRI beta subunit-ITAM (ITAM motif) regulates degranulation and cytokine production positively and negatively depending on the intensity of FcepsilonRI stimulation. Furthermore, Lyn-mediated negative regulation was shown to be exerted via the FcepsilonRI beta-ITAM.
Xiao
Wenbin
W
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
Nishimoto
Hajime
H
Hong
Hong
H
Kitaura
Jiro
J
Nunomura
Satoshi
S
Maeda-Yamamoto
Mari
M
Kawakami
Yuko
Y
Lowell
Clifford A
CA
Ra
Chisei
C
Kawakami
Toshiaki
T
D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D015550:Cell Degranulation; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D007073:Immunoglobulin E / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011940:Receptor Aggregation; D017455:Receptors, IgE / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D000941:Antigens; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D017455:Receptors, IgE; D007073:Immunoglobulin E; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; D010744:Phosphoric Monoester Hydrolases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases