Liang Xuan, Budnar Srikanth, Gupta Shafali, Verma Suzie, Han Siew-Ping, Hill Michelle M, Daly Roger J, Parton Robert G, Hamilton Nicholas A, Gomez Guillermo A, Yap Alpha S
Division of Cell Biology and Molecular Medicine, The University of Queensland, St. Lucia, QLD, 4072, Australia.
The University of Queensland Diamantina Institute, Brisbane, QLD, 4102, Australia.
Nat Commun. 2017 Oct 5;8(1):790. doi: 10.1038/s41467-017-00797-w.
Contractile adherens junctions support cell-cell adhesion, epithelial integrity, and morphogenesis. Much effort has been devoted to understanding how contractility is established; however, less is known about whether contractility can be actively downregulated at junctions nor what function this might serve. We now identify such an inhibitory pathway that is mediated by the cytoskeletal scaffold, cortactin. Mutations of cortactin that prevent its tyrosine phosphorylation downregulate RhoA signaling and compromise the ability of epithelial cells to generate a contractile zonula adherens. This is mediated by the RhoA antagonist, SRGAP1. We further demonstrate that this mechanism is co-opted by hepatocyte growth factor to promote junctional relaxation and motility in epithelial collectives. Together, our findings identify a novel function of cortactin as a regulator of RhoA signaling that can be utilized by morphogenetic regulators for the active downregulation of junctional contractility.Epithelial cell-cell adhesions are contractile junctions, but whether contractility can be down-regulated is not known. Here the authors report how tyrosine dephosphorylation of the cytoskeletal scaffold, cortactin, recruits the RhoA antagonist SRGAP1 to relax adherens junctions in response to HGF.
收缩性黏附连接支持细胞间黏附、上皮完整性和形态发生。人们已投入大量精力来理解收缩性是如何建立的；然而，对于收缩性是否能在连接处被主动下调以及这可能具有何种功能却知之甚少。我们现在鉴定出了这样一条由细胞骨架支架蛋白——皮层肌动蛋白介导的抑制性途径。阻止皮层肌动蛋白酪氨酸磷酸化的突变会下调RhoA信号，并损害上皮细胞产生收缩性黏着小带的能力。这是由RhoA拮抗剂SRGAP1介导的。我们进一步证明，肝细胞生长因子利用这种机制来促进上皮细胞群体中的连接松弛和迁移。总之，我们的研究结果确定了皮层肌动蛋白作为RhoA信号调节因子的新功能，形态发生调节因子可利用该功能来主动下调连接收缩性。上皮细胞间黏附是收缩性连接，但收缩性是否能被下调尚不清楚。本文作者报道了细胞骨架支架蛋白皮层肌动蛋白的酪氨酸去磷酸化如何招募RhoA拮抗剂SRGAP1，以响应肝细胞生长因子来松弛黏附连接。
