The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor

Peilin Ma, Raghuveer Singh Mali, Veerendra Munugalavadla, Subha Krishnan, Baskar Ramdas, Emily Sims, Holly Martin, Joydeep Ghosh, Shuo Li, Rebecca J. Chan, Gerald Krystal, Andrew W. Craig, Clifford M Takemoto, Reuben Kapur

Research output: Contribution to journalArticle

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 rescuesthe 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.

Original languageEnglish (US)
Pages (from-to)3459-3469
Number of pages11
JournalBlood
Volume118
Issue number13
DOIs
StatePublished - Sep 29 2011

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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  • Cite this

    Ma, P., Mali, R. S., Munugalavadla, V., Krishnan, S., Ramdas, B., Sims, E., Martin, H., Ghosh, J., Li, S., Chan, R. J., Krystal, G., Craig, A. W., Takemoto, C. M., & Kapur, R. (2011). The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor. Blood, 118(13), 3459-3469. https://doi.org/10.1182/blood-2011-04-351809