Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Institute for Genetic Medicine, Division of Molecular Oncology, Hokkaido University, Sapporo, Japan.
Life Sci Alliance. 2019 Feb 13;2(1). doi: 10.26508/lsa.201800276. Print 2019 Feb.
Epithelial cells form sheets and tubules in various epithelial organs and establish apicobasal polarity and asymmetric vesicle transport to provide functionality in these structures. However, the molecular mechanisms that allow epithelial cells to establish polarity are not clearly understood. Here, we present evidence that the kinase activity of the receptor tyrosine kinase for collagen, discoidin domain receptor 1 (DDR1), is required for efficient establishment of epithelial polarity, proper asymmetric protein secretion, and execution of morphogenic programs. Lack of DDR1 protein or inhibition of DDR1 kinase activity disturbed tubulogenesis, cystogenesis, and the establishment of epithelial polarity and caused defects in the polarized localization of membrane-type 1 matrix metalloproteinase (MT1-MMP), GP135, primary cilia, laminin, and the Golgi apparatus. Disturbed epithelial polarity and cystogenesis upon DDR1 inhibition was caused by excess ROCK (rho-associated, coiled-coil-containing protein kinase)-driven actomyosin contractility, and pharmacological inhibition of ROCK was sufficient to correct these defects. Our data indicate that a DDR1-ROCK signaling axis is essential for the efficient establishment of epithelial polarity.
上皮细胞在各种上皮器官中形成片层和管状结构，并建立顶端-基底极性和不对称囊泡运输，以提供这些结构的功能。然而，允许上皮细胞建立极性的分子机制尚不清楚。在这里，我们提供的证据表明，胶原受体酪氨酸激酶 discoidin 结构域受体 1（DDR1）的激酶活性对于有效建立上皮极性、适当的不对称蛋白分泌以及形态发生程序的执行是必需的。缺乏 DDR1 蛋白或抑制 DDR1 激酶活性会扰乱小管形成、囊泡形成以及上皮极性的建立，并导致膜型 1 基质金属蛋白酶（MT1-MMP）、GP135、初级纤毛、层粘连蛋白和高尔基体的极化定位缺陷。DDR1 抑制后上皮极性和囊泡形成的紊乱是由过量的 ROCK（rho 相关卷曲螺旋蛋白激酶）驱动的肌动球蛋白收缩引起的，而 ROCK 的药理学抑制足以纠正这些缺陷。我们的数据表明，DDR1-ROCK 信号轴对于有效建立上皮极性是必不可少的。
