Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden.
Medical Biochemistry and Biophysics, Laboratory for Molecular Infection Medicine Sweden, Umeå University, 901 87 Umeå, Sweden.
Cell Rep. 2017 Aug 22;20(8):1893-1905. doi: 10.1016/j.celrep.2017.08.006.
Cellular blebbing, caused by local alterations in cell-surface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrin-independent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension-mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol-interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.
细胞起泡是由于细胞表面张力的局部改变引起的，已被证明会增加癌细胞的侵袭性。然而，平衡细胞表面动力学和起泡形成的调节机制仍然难以捉摸。在这里，我们表明细胞体积的急性减少会激活网格蛋白非依赖性内吞作用。因此，通过内化质膜（PM）脂质双层来缓冲表面张力的降低。膜内陷和内吞作用是由张力介导的膜造型和 GTPase 激活蛋白 GRAF1（与粘着斑激酶-1 相关的 GTPase 调节因子）向 PM 的募集驱动的。通过耗尽细胞中的 GRAF1 或突变蛋白质中关键的与磷脂酰肌醇相互作用的氨基酸来破坏这种调节，会导致细胞起泡增加，并促进癌细胞的 3D 运动性。我们的数据支持网格蛋白非依赖性内吞机制在平衡膜张力中的作用，这阐明了 GRAF1 作为肿瘤抑制因子的先前报道的作用。
