Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA.
Dev Biol. 2013 Jul 15;379(2):235-45. doi: 10.1016/j.ydbio.2013.04.029. Epub 2013 May 7.
The tree-like architecture of the mammary gland is generated by branching morphogenesis, which is regulated by many signals from the microenvironment. Here we examined how signaling downstream of phosphoinositide 3-kinase (PI3K) regulates different steps of mammary branching using three-dimensional culture models of the mammary epithelial duct. We found that PI3K was required for both branch initiation and elongation. Activated Akt was enhanced at branch initiation sites where its negative regulator, PTEN, was blocked by signaling via Sprouty2 (SPRY2); inhibiting Akt prevented branch initiation. The pattern of SPRY2 expression, and thus of Akt activation and branch initiation, was controlled by mechanical signaling from endogenous cytoskeletal contractility. In contrast, activated GTP-bound Rac1 localized to the leading edge of nascent branches and was required for branch elongation. These data suggest that the PI3K network integrates mechanical and biochemical signaling to control branching morphogenesis of mammary epithelial cells.
乳腺的树状结构是通过分支形态发生产生的，这一过程受到来自微环境的多种信号的调节。在这里，我们使用乳腺上皮导管的三维培养模型，研究了磷酸肌醇 3-激酶 (PI3K) 信号通路下游的信号如何调节乳腺分支的不同步骤。我们发现 PI3K 对于分支起始和延伸都是必需的。在分支起始位点，Akt 被激活，其负调节因子 PTEN 被通过 Sprouty2 (SPRY2) 信号阻断；抑制 Akt 则阻止了分支起始。SPRY2 表达的模式，以及 Akt 的激活和分支起始，受到来自内源性细胞骨架收缩的机械信号的控制。相比之下，活化的 GTP 结合 Rac1 定位于新分支的前缘，并且是分支延伸所必需的。这些数据表明，PI3K 网络整合了机械和生化信号，以控制乳腺上皮细胞的分支形态发生。
