TY - JOUR
T1 - The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor
AU - Ma, Peilin
AU - Mali, Raghuveer Singh
AU - Munugalavadla, Veerendra
AU - Krishnan, Subha
AU - Ramdas, Baskar
AU - Sims, Emily
AU - Martin, Holly
AU - Ghosh, Joydeep
AU - Li, Shuo
AU - Chan, Rebecca J.
AU - Krystal, Gerald
AU - Craig, Andrew W.
AU - Takemoto, Clifford M
AU - Kapur, Reuben
PY - 2011/9/29
Y1 - 2011/9/29
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2011-04-351809
DO - 10.1182/blood-2011-04-351809
M3 - Article
C2 - 21791431
AN - SCOPUS:80053343769
SN - 0006-4971
VL - 118
SP - 3459
EP - 3469
JO - Blood
JF - Blood
IS - 13
ER -