PMID- 30563863 OWN - NLM STAT- MEDLINE DCOM- 20191025 LR - 20220716 IS - 1937-9145 (Electronic) IS - 1945-0877 (Print) IS - 1945-0877 (Linking) VI - 11 IP - 561 DP - 2018 Dec 18 TI - CD45 exclusion- and cross-linking-based receptor signaling together broaden FcepsilonRI reactivity. LID - 10.1126/scisignal.aat0756 [doi] LID - eaat0756 AB - For many years, the high-affinity receptor for immunoglobulin E (IgE) FcepsilonRI, which is expressed by mast cells and basophils, has been widely held to be the exemplar of cross-linking (that is, aggregation dependent) signaling receptors. We found, however, that FcepsilonRI signaling could occur in the presence or absence of receptor cross-linking. Using both cell and cell-free systems, we showed that FcepsilonRI signaling was stimulated by surface-associated monovalent ligands through the passive, size-dependent exclusion of the receptor-type tyrosine phosphatase CD45 from plasma membrane regions of FcepsilonRI-ligand engagement. Similarly to the T cell receptor, FcepsilonRI signaling could also be initiated in a ligand-independent manner. These data suggest that a simple mechanism of CD45 exclusion-based receptor triggering could function together with cross-linking-based FcepsilonRI signaling, broadening mast cell and basophil reactivity by enabling these cells to respond to both multivalent and surface-presented monovalent antigens. These findings also strengthen the case that a size-dependent, phosphatase exclusion-based receptor triggering mechanism might serve generally to facilitate signaling by noncatalytic immune receptors. CI - Copyright (c) 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. FAU - Felce, James H AU - Felce JH AUID- ORCID: 0000-0001-5531-9244 AD - MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. AD - Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK. AD - Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK. FAU - Sezgin, Erdinc AU - Sezgin E AUID- ORCID: 0000-0002-4915-388X AD - MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. FAU - Wane, Madina AU - Wane M AUID- ORCID: 0000-0002-7647-0194 AD - MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. AD - Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK. FAU - Brouwer, Heather AU - Brouwer H AUID- ORCID: 0000-0003-3840-6834 AD - MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. AD - Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK. FAU - Dustin, Michael L AU - Dustin ML AUID- ORCID: 0000-0003-4983-6389 AD - Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK. simon.davis@imm.ox.ac.uk christian.eggeling@rdm.ox.ac.uk michael.dustin@kennedy.ox.ac.uk. FAU - Eggeling, Christian AU - Eggeling C AUID- ORCID: 0000-0002-3698-5599 AD - MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. simon.davis@imm.ox.ac.uk christian.eggeling@rdm.ox.ac.uk michael.dustin@kennedy.ox.ac.uk. FAU - Davis, Simon J AU - Davis SJ AUID- ORCID: 0000-0002-2280-1170 AD - MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. simon.davis@imm.ox.ac.uk christian.eggeling@rdm.ox.ac.uk michael.dustin@kennedy.ox.ac.uk. AD - Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK. LA - eng GR - MC_UU_12010/4/MRC_/Medical Research Council/United Kingdom GR - 098274/Z/12/Z/WT_/Wellcome Trust/United Kingdom GR - MR/K01577X/1/MRC_/Medical Research Council/United Kingdom GR - 104924/14/Z/14/WT_/Wellcome Trust/United Kingdom GR - 091911/WT_/Wellcome Trust/United Kingdom GR - 100262/Z/12/Z/WT_/Wellcome Trust/United Kingdom GR - MC_UU_12010/9/MRC_/Medical Research Council/United Kingdom GR - 207547/Z/17/Z/WT_/Wellcome Trust/United Kingdom GR - WT_/Wellcome Trust/United Kingdom GR - 107375/Z/15/Z/WT_/Wellcome Trust/United Kingdom GR - 207547/WT_/Wellcome Trust/United Kingdom GR - MC_UU_12025/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00008/4/MRC_/Medical Research Council/United Kingdom GR - MC_UU_00008/9/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181218 PL - United States TA - Sci Signal JT - Science signaling JID - 101465400 RN - 0 (Cross-Linking Reagents) RN - 0 (FCER1A protein, rat) RN - 0 (Integrins) RN - 0 (Receptors, IgE) RN - 37341-29-0 (Immunoglobulin E) RN - EC 3.1.3.48 (Leukocyte Common Antigens) RN - EC 3.1.3.48 (Ptprc protein, rat) SB - IM MH - Animals MH - CRISPR-Cas Systems MH - *Cell Degranulation MH - Cross-Linking Reagents/chemistry MH - Immunoglobulin E/*metabolism MH - Integrins/metabolism MH - Leukemia, Basophilic, Acute/*immunology/metabolism/pathology MH - Leukocyte Common Antigens/genetics/*metabolism MH - Mast Cells/*immunology/metabolism MH - Rats MH - Receptors, IgE/antagonists & inhibitors/genetics/*metabolism MH - Tumor Cells, Cultured PMC - PMC7612966 MID - EMS146274 COIS- Competing interests: The authors declare that they have no competing interests. EDAT- 2018/12/20 06:00 MHDA- 2019/10/28 06:00 PMCR- 2022/07/04 CRDT- 2018/12/20 06:00 PHST- 2018/12/20 06:00 [entrez] PHST- 2018/12/20 06:00 [pubmed] PHST- 2019/10/28 06:00 [medline] PHST- 2022/07/04 00:00 [pmc-release] AID - 11/561/eaat0756 [pii] AID - 10.1126/scisignal.aat0756 [doi] PST - epublish SO - Sci Signal. 2018 Dec 18;11(561):eaat0756. doi: 10.1126/scisignal.aat0756.