Purvanov Vladimir, Holst Manuel, Khan Jameel, Baarlink Christian, Grosse Robert
Institute of Pharmacology, University of Marburg, Marburg, Germany.
Elife. 2014 Jun 20;3:e02786. doi: 10.7554/eLife.02786.
Homotypic or entotic cell-in-cell invasion is an integrin-independent process observed in carcinoma cells exposed during conditions of low adhesion such as in exudates of malignant disease. Although active cell-in-cell invasion depends on RhoA and actin, the precise mechanism as well as the underlying actin structures and assembly factors driving the process are unknown. Furthermore, whether specific cell surface receptors trigger entotic invasion in a signal-dependent fashion has not been investigated. In this study, we identify the G-protein-coupled LPA receptor 2 (LPAR2) as a signal transducer specifically required for the actively invading cell during entosis. We find that G12/13 and PDZ-RhoGEF are required for entotic invasion, which is driven by blebbing and a uropod-like actin structure at the rear of the invading cell. Finally, we provide evidence for an involvement of the RhoA-regulated formin Dia1 for entosis downstream of LPAR2. Thus, we delineate a signaling process that regulates actin dynamics during cell-in-cell invasion.
同型或内吞性细胞-细胞侵袭是一种不依赖整合素的过程，在低黏附条件下（如恶性疾病渗出液中）暴露的癌细胞中观察到。虽然活跃的细胞-细胞侵袭依赖于RhoA和肌动蛋白，但驱动该过程的精确机制以及潜在的肌动蛋白结构和组装因子尚不清楚。此外，特定细胞表面受体是否以信号依赖方式触发内吞性侵袭尚未得到研究。在本研究中，我们确定G蛋白偶联的溶血磷脂酸受体2（LPAR2）是内吞过程中活跃侵袭细胞特别需要的信号转导分子。我们发现G12/13和PDZ-RhoGEF是内吞性侵袭所必需的，这是由侵袭细胞后部的气泡形成和尾足样肌动蛋白结构驱动的。最后，我们提供证据表明RhoA调节的formin Dia1参与LPAR2下游的内吞过程。因此，我们描绘了一个在细胞-细胞侵袭过程中调节肌动蛋白动力学的信号传导过程。
