Calcineurin-Rcan1 interaction contributes to stem cell factor-mediated mast cell activation.
The receptor for stem cell factor (SCF) is expressed on mast cells and hematopoietic progenitors. SCF-induced signaling pathways remain incompletely defined. In this study, we identified calcineurin and regulator of calcineurin 1 (Rcan1) as novel components in SCF signaling. Calcineurin activity was induced in SCF-stimulated primary mouse and human mast cells. NFAT was activated by SCF in bone marrow-derived mast cells (BMMCs) and mouse bone marrow cells, which contain hematopoietic progenitors. SCF-mediated activation also induced expression of Rcan1 in BMMCs. Rcan1-deficient BMMCs showed increased calcineurin activity and enhanced transcriptional activity of NF-κB and NFAT, resulting in increased IL-6 and TNF production following SCF stimulation. These results suggest that Rcan1 suppresses SCF-induced activation of calcineurin and NF-κB. We further demonstrated that SCF-induced Rcan1 expression is dependent on the transcription factor early growth response 1 (Egr1). Interestingly, SCF-induced Egr1 was also suppressed by Rcan1, suggesting a negative regulatory loop between Egr1 and Rcan1. Together, our findings revealed that calcineurin contributes to SCF-induced signaling, leading to NFAT activation, which, together with NF-κB and Egr1, is suppressed by Rcan1. Considering the wide range of biological functions of SCF, these novel regulatory mechanisms in SCF signaling may have broad implications.
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada.
Zhengli
Z
Wu
Yanhong
Y
Li
Adam J
AJ
MacNeil
Robert D
RD
Junkins
Jason N
JN
Berman
Tong-Jun
TJ
Lin
D000818:Animals; D001854:Bone Marrow Cells; D019703:Calcineurin / Q000502:physiology*; D065095:Calcineurin Inhibitors; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1 / Q000502:physiology; D025461:Feedback, Physiological; D005312:Fetal Blood / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019089:Stem Cell Factor / Q000494:pharmacology / Q000502:physiology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D065095:Calcineurin Inhibitors; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C511512:DSCR1 protein, mouse; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; C108612:RCAN1 protein, human; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D019009:Proto-Oncogene Proteins c-kit; D019703:Calcineurin