title: The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor.
abstract: Mast cell maturation is poorly understood. We show that enhanced PI3K activation results in accelerated maturation of mast cells by inducing the expression of microphthalmia transcription factor (Mitf). Conversely, loss of PI3K activation reduces the maturation of mast cells by inhibiting the activation of AKT, leading to reduced Mitf but enhanced Gata-2 expression and accumulation of Gr1(+)Mac1(+) myeloid cells as opposed to mast cells. Consistently, overexpression of Mitf accelerates the maturation of mast cells, whereas Gata-2 overexpression mimics the loss of the PI3K phenotype. Expressing the full-length or the src homology 3- or BCR homology domain-deleted or shorter splice variant of the p85α regulatory subunit of PI3K or activated AKT or Mitf in p85α-deficient cells restores the maturation but not growth. Although deficiency of both SHIP and p85α rescues the maturation of SHIP(-/-) and p85α(-/-) mast cells and expression of Mitf; in vivo, mast cells are rescued in some, but not all tissues, due in part to defective KIT signaling, which is dependent on an intact src homology 3 and BCR homology domain of p85α. Thus, p85α-induced maturation, and growth and survival signals, in mast cells can be uncoupled.
authors.affiliation: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indianapolis, IN, USA.
authors.forename: Peilin
authors.initials: P
authors.lastname: Ma
authors.forename: Raghuveer Singh
authors.initials: RS
authors.lastname: Mali
authors.forename: Veerendra
authors.initials: V
authors.lastname: Munugalavadla
authors.forename: Subha
authors.initials: S
authors.lastname: Krishnan
authors.forename: Baskar
authors.initials: B
authors.lastname: Ramdas
authors.forename: Emily
authors.initials: E
authors.lastname: Sims
authors.forename: Holly
authors.initials: H
authors.lastname: Martin
authors.forename: Joydeep
authors.initials: J
authors.lastname: Ghosh
authors.forename: Shuo
authors.initials: S
authors.lastname: Li
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Craig
authors.forename: Clifford
authors.initials: C
authors.lastname: Takemoto
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics* / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D008407:Mast Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014162:Transfection
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D019869:Phosphatidylinositol 3-Kinases