title: Class I PI3K-mediated Akt and ERK signals play a critical role in FcεRI-induced degranulation in mast cells.
abstract: Class IA and IB phosphoinositide 3-kinases (PI3Ks) have been shown to regulate mast cell functions such as proliferation, development, survival and degranulation, but the functional redundancy between these two PI3K signaling pathways in mast cells remains unclear. Here, we have generated mice deficient in both class IA regulatory subunit p85α and class IB catalytic subunit p110γ, and show that p85α(-/-)p110γ(-/-) mice exhibit a more severe defect in mast cell development than single-knockout mice. In addition, the in vivo passive cutaneous anaphylaxis reaction of p85α(-/-)p110γ(-/-) mice was nearly completely abrogated, whereas single-knockout mice exhibit just marginal reduction. Pharmacological inactivation of Akt in wild-type bone marrow-derived mast cells (BMMCs) led to partial reduction of degranulation, while over-expression of a constitutively active Akt partially restored the impaired degranulation in p85α(-/-)p110γ(-/-) BMMCs. We also found that the extracellular signal-regulated kinase (ERK) signaling pathway was activated in a PI3K-dependent manner upon FcεRI stimulation and that simultaneous inhibition of Akt and ERK resulted in nearly complete blockade of FcεRI-induced degranulation. Our data provide evidence that Akt and ERK pathways play redundant roles in FcεRI-induced degranulation.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Gensuke
authors.initials: G
authors.lastname: Takayama
authors.forename: Masashi
authors.initials: M
authors.lastname: Ohtani
authors.forename: Akiko
authors.initials: A
authors.lastname: Minowa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuda
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
mesh_terms: D000818:Animals; D015550:Cell Degranulation; D002478:Cells, Cultured; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism*; D010323:Passive Cutaneous Anaphylaxis / Q000276:immunology*; D017455:Receptors, IgE / Q000276:immunology*; D019076:Transgenes / Q000235:genetics
chemical_list: D017455:Receptors, IgE; D058543:Class Ia Phosphatidylinositol 3-Kinase; D058544:Class Ib Phosphatidylinositol 3-Kinase; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases