Balanced interactions between Lyn, the p85α Regulatory Subunit of Class I A phosphatidylinositol-3-kinase, and SHIP Are essential for mast cell growth and maturation

Peilin Ma, Sasidhar Vemula, Veerendra Munugalavadla, Jinbiao Chen, Emily Sims, Jovencio Borneo, Takako Kondo, Baskar Ramdas, Raghuveer Singh Mali, Shuo Li, Eri Hashino, Clifford Takemoto, Reuben Kapur

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The growth and maturation of bone marrow-derived mast cells (BMMCs) from precursors are regulated by coordinated signals from multiple cytokine receptors, including KIT. While studies conducted using mutant forms of these receptors lacking the binding sites for Src family kinases (SFKs) and phosphatidylinositol-3-kinase (PI3K) suggest a role for these signaling molecules in regulating growth and survival, how complete loss of these molecules in early BMMC progenitors (MCps) impacts maturation and growth during all phases of mast cell development is not fully understood. We show that the Lyn SFK and the p85α subunit of class IA PI3K play opposing roles in regulating the growth and maturation of BMMCs in part by regulating the level of PI3K. Loss of Lyn in BMMCs results in elevated PI3K activity and hyperactivation of AKT, which accelerates the rate of BMMC maturation due in part to impaired binding and phosphorylation of SHIP via Lyn's unique domain. In the absence of Lyn's unique domain, BMMCs behave in a manner similar to that of Lyn- or SHIP-deficient BMMCs. Importantly, loss of p85α in Lyn-deficient BMMCs not only represses the hyperproliferation associated with the loss of Lyn but also represses their accelerated maturation. The accelerated maturation of BMMCs due to loss of Lyn is associated with increased expression of microphthalmia-associated transcription factor (Mitf), which is repressed in MCps deficient in the expression of both Lyn and p85α relative to controls. Our results demonstrate a crucial interplay of Lyn, SHIP, and p85α in regulating the normal growth and maturation of BMMCs, in part by regulating the activation of AKT and the expression of Mitf.

Original languageEnglish (US)
Pages (from-to)4052-4062
Number of pages11
JournalMolecular and cellular biology
Volume31
Issue number19
DOIs
StatePublished - Oct 1 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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