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

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 p85 alpha regulatory subunit of PI3K or activated AKT or Mitf in p85 alpha-deficient cells restores the maturation but not growth. Although deficiency of both SHIP and p85 alpha rescues the maturation of SHIP(-/-) and p85 alpha(-/-) 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 p85 alpha. Thus, p85 alpha-induced maturation, and growth and survival signals, in mast cells can be uncoupled. (Blood. 2011;118(13):3459-3469)