磷脂酰肌醇3激酶调节亚型在发育和肌动蛋白重排中的作用。
Role of phosphoinositide 3-kinase regulatory isoforms in development and actin rearrangement.
作者信息
Brachmann Saskia M, Yballe Claudine M, Innocenti Metello, Deane Jonathan A, Fruman David A, Thomas Sheila M, Cantley Lewis C
机构信息
Beth Israel Hospital, NRB, Division of Signal Transduction, Department of Systems Biology,10th Floor, 330 Brookline, MA 02215, USA.
出版信息
Mol Cell Biol. 2005 Apr;25(7):2593-606. doi: 10.1128/MCB.25.7.2593-2606.2005.
Class Ia phosphoinositide 3-kinases (PI3Ks) are heterodimers of p110 catalytic and p85 regulatory subunits that mediate a variety of cellular responses to growth and differentiation factors. Although embryonic development is not impaired in mice lacking all isoforms of the p85alpha gene (p85alpha-/- p55alpha-/- p50alpha-/-) or in mice lacking the p85beta gene (p85beta-/-) (D. A. Fruman, F. Mauvais-Jarvis, D. A. Pollard, C. M. Yballe, D. Brazil, R. T. Bronson, C. R. Kahn, and L. C. Cantley, Nat Genet. 26:379-382, 2000; K. Ueki, C. M. Yballe, S. M. Brachmann, D. Vicent, J. M. Watt, C. R. Kahn, and L. C. Cantley, Proc. Natl. Acad. Sci. USA 99:419-424, 2002), we show here that loss of both genes results in lethality at embryonic day 12.5 (E12.5). The phenotypes of these embryos, including subepidermal blebs flanking the neural tube at E8 and bleeding into the blebs during the turning process, are similar to defects observed in platelet-derived growth factor receptor alpha null (PDGFRalpha-/-) mice (P. Soriano, Development 124:2691-2700, 1997), suggesting that PI3K is an essential mediator of PDGFRalpha signaling at this developmental stage. p85alpha-/- p55alpha+/+ p50alpha+/+ p85beta-/- mice had similar but less severe defects, indicating that p85alpha and p85beta have a critical and redundant function in development. Mouse embryo fibroblasts deficient in all p85alpha and p85beta gene products (p85alpha-/- p55alpha-/- p50alpha-/- p85beta-/-) are defective in PDGF-induced membrane ruffling. Overexpression of the Rac-specific GDP-GTP exchange factor Vav2 or reintroduction of p85alpha or p85beta rescues the membrane ruffling defect. Surprisingly, reintroduction of p50alpha also restored PDGF-dependent membrane ruffling. These results indicate that class Ia PI3K is critical for PDGF-dependent actin rearrangement but that the SH3 domain and the Rho/Rac/Cdc42-interacting domain of p85, which lacks p50alpha, are not required for this response.
I 类磷酸肌醇 3 -激酶（PI3K）是由 p110 催化亚基和 p85 调节亚基组成的异二聚体，介导细胞对生长和分化因子的多种反应。尽管缺乏 p85α 基因所有亚型的小鼠（p85α-/- p55α-/- p50α-/-）或缺乏 p85β 基因的小鼠（p85β-/-）的胚胎发育未受损（D. A. 弗鲁曼、F. 莫韦 - 贾维斯、D. A. 波拉德、C. M. 亚勒、D. 巴西、R. T. 布朗森、C. R. 卡恩和 L. C. 坎特利，《自然遗传学》。26:379 - 382，2000；K. 上eki、C. M.亚勒、S. M. 布拉赫曼、D. 维森特、J. M. 瓦特、C. R. 卡恩和 L. C. 坎特利，《美国国家科学院院刊》99:419 - 424，2002），但我们在此表明，两个基因的缺失会导致胚胎在第 12.5 天（E12.5）死亡。这些胚胎的表型，包括在 E8 时神经管两侧的表皮下泡以及在胚胎翻转过程中血液渗入泡中，与在血小板衍生生长因子受体α缺失（PDGFRα-/-）小鼠中观察到的缺陷相似（P. 索里亚诺，《发育》124:2691 - 2700，1997），这表明 PI3K 是该发育阶段 PDGFRα 信号传导的关键介质。p85α-/- p55α+/+ p50α+/+ p85β-/- 小鼠有类似但不太严重的缺陷，表明 p85α 和 p85β 在发育中具有关键且冗余的功能。缺乏所有 p85α 和 p85β 基因产物的小鼠胚胎成纤维细胞（p85α-/- p55α-/- p50α-/- p85β-/-）在 PDGF 诱导的膜皱襞形成方面存在缺陷。Rac 特异性 GDP - GTP 交换因子 Vav2 的过表达或 p85α 或 p85β 的重新引入可挽救膜皱襞形成缺陷。令人惊讶的是，p50α 的重新引入也恢复了 PDGF 依赖性的膜皱襞形成。这些结果表明，I 类 PI3K 对 PDGF 依赖性肌动蛋白重排至关重要，但缺乏 p50α 的 p85 的 SH3 结构域和 Rho/Rac/Cdc42 相互作用结构域对此反应并非必需。
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