Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W. Walnut Street, Indianapolis, IN 46202, USA.
Mol Cell Biol. 2011 Oct;31(19):4052-62. doi: 10.1128/MCB.05750-11. Epub 2011 Jul 26.
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 I(A) 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.
骨髓来源的肥大细胞（BMMC）由前体细胞生长和成熟受到多种细胞因子受体（包括 KIT）的协调信号的调节。虽然使用缺乏Src 家族激酶（SFKs）和磷脂酰肌醇-3-激酶（PI3K）结合位点的这些受体的突变形式进行的研究表明这些信号分子在调节生长和存活方面发挥作用，但这些分子在早期 BMMC 祖细胞（MCps）中的完全缺失如何影响肥大细胞发育的所有阶段中的成熟和生长尚不完全清楚。我们表明，Lyn SFK 和 I 类（A）PI3K 的 p85α 亚基通过调节 PI3K 的水平在调节 BMMC 的生长和成熟方面发挥相反的作用。BMMC 中 Lyn 的缺失导致 PI3K 活性升高和 AKT 的过度激活，这部分由于通过 Lyn 的独特结构域 SHIP 的结合和磷酸化受损，从而加速 BMMC 的成熟速度。在缺乏 Lyn 的独特结构域的情况下，BMMC 的行为类似于 Lyn 或 SHIP 缺陷型 BMMC。重要的是，在缺乏 Lyn 的情况下，p85α 的缺失不仅抑制了与 Lyn 缺失相关的过度增殖，而且还抑制了它们的加速成熟。由于 Lyn 的缺失导致的 BMMC 的加速成熟与小眼畸形相关转录因子（Mitf）的表达增加有关，与对照相比，Lyn 和 p85α 表达缺陷的 MCps 中的 Mitf 表达受到抑制。我们的结果表明，Lyn、SHIP 和 p85α 在调节 BMMC 的正常生长和成熟方面存在着至关重要的相互作用，部分是通过调节 AKT 的激活和 Mitf 的表达来实现的。
