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 Chan, Gerald Krystal, Andrew W. Craig, Clifford Takemoto, Reuben Kapur

Research output: Contribution to journalArticle

15 Citations (Scopus)

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

Fingerprint

Microphthalmia-Associated Transcription Factor
Phosphatidylinositol 3-Kinases
Mast Cells
Chemical activation
Tissue
Myeloid Cells
Growth
Phenotype

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Ma, P., Mali, R. S., Munugalavadla, V., Krishnan, S., Ramdas, B., Sims, E., ... 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

The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor. / Ma, Peilin; Mali, Raghuveer Singh; Munugalavadla, Veerendra; Krishnan, Subha; Ramdas, Baskar; Sims, Emily; Martin, Holly; Ghosh, Joydeep; Li, Shuo; Chan, Rebecca; Krystal, Gerald; Craig, Andrew W.; Takemoto, Clifford; Kapur, Reuben.

In: Blood, Vol. 118, No. 13, 29.09.2011, p. 3459-3469.

Research output: Contribution to journalArticle

Ma, P, Mali, RS, Munugalavadla, V, Krishnan, S, Ramdas, B, Sims, E, Martin, H, Ghosh, J, Li, S, Chan, R, Krystal, G, Craig, AW, Takemoto, C & Kapur, R 2011, 'The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor', Blood, vol. 118, no. 13, pp. 3459-3469. https://doi.org/10.1182/blood-2011-04-351809
Ma P, Mali RS, Munugalavadla V, Krishnan S, Ramdas B, Sims E et al. The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor. Blood. 2011 Sep 29;118(13):3459-3469. https://doi.org/10.1182/blood-2011-04-351809
Ma, Peilin ; Mali, Raghuveer Singh ; Munugalavadla, Veerendra ; Krishnan, Subha ; Ramdas, Baskar ; Sims, Emily ; Martin, Holly ; Ghosh, Joydeep ; Li, Shuo ; Chan, Rebecca ; Krystal, Gerald ; Craig, Andrew W. ; Takemoto, Clifford ; Kapur, Reuben. / The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor. In: Blood. 2011 ; Vol. 118, No. 13. pp. 3459-3469.
@article{19a741607a2d48e49ab9042b3243eeeb,
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 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.",
author = "Peilin Ma and Mali, {Raghuveer Singh} and Veerendra Munugalavadla and Subha Krishnan and Baskar Ramdas and Emily Sims and Holly Martin and Joydeep Ghosh and Shuo Li and Rebecca Chan and Gerald Krystal and Craig, {Andrew W.} and Clifford Takemoto and Reuben Kapur",
year = "2011",
month = "9",
day = "29",
doi = "10.1182/blood-2011-04-351809",
language = "English",
volume = "118",
pages = "3459--3469",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "13",

}

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

AU - Krystal, Gerald

AU - Craig, Andrew W.

AU - Takemoto, Clifford

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.

UR - http://www.scopus.com/inward/record.url?scp=80053343769&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053343769&partnerID=8YFLogxK

U2 - 10.1182/blood-2011-04-351809

DO - 10.1182/blood-2011-04-351809

M3 - Article

C2 - 21791431

AN - SCOPUS:80053343769

VL - 118

SP - 3459

EP - 3469

JO - Blood

JF - Blood

SN - 0006-4971

IS - 13

ER -