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Intriguingly, IgE alone also stimulated massive degranulation in SHIP\u2212\/\u2212 but not in +\/+ mast cells. This degranulation with IgE alone, which may be due to low levels of IgE aggregates, correlated with a higher and more sustained intracellular calcium level than that observed with SHIP+\/+ cells and was dependent upon the entry of extracellular calcium. Immunoprecipitation studies revealed that the addition of IgE alone to normal mast cells stimulates multiple cascades, which are prevented from progressing to degranulation by SHIP. PI 3-kinase inhibitor studies suggested that IgE-induced activation of PI 3-kinase is upstream of the entry of extracellular calcium and that SHIP restricts this entry by hydrolyzing phosphatidylinositol 3,4,5-trisphosphate. These results show the critical role that SHIP plays in setting the threshold for degranulation and that SHIP directly modulates a \u201cpositive-acting\u201d receptor.<\/jats:p>","DOI":"10.1073\/pnas.95.19.11330","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T14:40:11Z","timestamp":1027694411000},"page":"11330-11335","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":238,"title":["The src homology 2-containing inositol phosphatase (SHIP) is the gatekeeper of mast cell degranulation"],"prefix":"10.1073","volume":"95","author":[{"given":"Michael","family":"Huber","sequence":"first","affiliation":[{"name":"Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3"}]},{"given":"Cheryl D.","family":"Helgason","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3"}]},{"given":"Jacqueline E.","family":"Damen","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3"}]},{"given":"Ling","family":"Liu","sequence":"additional","affiliation":[{"name":"Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3"}]},{"given":"R. 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