Dept. of Anatomy, University of California San Francisco, CA 94158-2140, USA; Dept. of Biochemistry and Biophysics, University of California San Francisco, CA 94158-2140, USA.
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom.
Cell Signal. 2017 Dec;40:91-98. doi: 10.1016/j.cellsig.2017.09.001. Epub 2017 Sep 6.
The formation of lumens in epithelial tissues requires apical-basal polarization of cells, and the co-ordination of this individual polarity collectively around a contiguous lumen. Signals from the Extracellular Matrix (ECM) instruct epithelia as to the orientation of where basal, and thus consequently apical, surfaces should be formed. We report that this pathway is normally absent in Calu-3 human lung adenocarcinoma cells in 3-Dimensional culture, but that paracrine signals from MRC5 lung fibroblasts can induce correct orientation of polarity and acinar morphogenesis. We identify HGF, acting through the c-Met receptor, as the key polarity-inducing morphogen, which acts to activate β1-integrin-dependent adhesion. HGF and ECM-derived integrin signals co-operate via a c-Src-dependent inhibition of the RhoA-ROCK1 signalling pathway via p190A RhoGAP. This occurred via controlling localization of these signalling pathways to the ECM-abutting surface of cells in 3-Dimensional culture. Thus, stromal derived signals can influence morphogenesis in epithelial cells by controlling activation and localization of cell polarity pathways.
上皮组织中管腔的形成需要细胞的顶-基底极性化，并且这种个体极性在连续的管腔周围协调。细胞外基质 (ECM) 的信号指示上皮细胞基底和随后的顶端表面应形成的方向。我们报告说，在三维培养的 Calu-3 人肺腺癌细胞中，该途径通常缺失，但 MRC5 肺成纤维细胞的旁分泌信号可以诱导极性的正确定向和腺泡形态发生。我们确定 HGF 通过 c-Met 受体起作用作为关键的极性诱导形态发生因子，其作用是激活β1-整联蛋白依赖性粘附。HGF 和 ECM 衍生的整联信号通过 c-Src 依赖性抑制 RhoA-ROCK1 信号通路通过 p190A RhoGAP 协同作用。这是通过控制这些信号通路在三维培养的细胞与 ECM 相邻的表面上的定位来实现的。因此，基质衍生的信号可以通过控制细胞极性途径的激活和定位来影响上皮细胞的形态发生。
