Department of Biochemistry and the Siebens-Drake Medical Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada N6A 5C1.
Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1455-60. doi: 10.1073/pnas.1114368109. Epub 2012 Jan 17.
The epithelial growth factor receptor plays an important role in cell migration and cancer metastasis, but the underlying molecular mechanism is not fully understood. We show here that differential regulation of the Ras-homology-GTPase-activating protein [corrected] (Rho-GAP) activity of deleted in liver cancer 1 (DLC1) by tensin3 and COOH-terminal tensin-like protein (cten) controls EGF-driven cell migration and transformation. Tensin3 binds DLC1 through its actin-binding domain, a region that is missing in cten, and thereby releases an autoinhibitory interaction between the sterile alpha motif and Rho-GAP domains of DLC1. Consequently, tensin3, but not cten, promotes the activation of DLC1, which, in turn, leads to inactivation of RhoA and decreased cell migration. Depletion of endogenous tensin3, but not cten, augmented the formation of actin stress fibers and focal adhesions and enhanced cell motility. These effects were, however, ablated by an inhibitor of the Rho-associated protein kinase. Importantly, activation of DLC1 by tensin3 or its actin-binding domain drastically reduced the anchorage-independent growth of transformed cells. Our study therefore links dynamic regulation of tensin family members by EGF to Rho-GAP through DLC1 and suggests that the tensin-DLC1-RhoA signaling axis plays an important role in tumorigenesis and cancer metastasis, and may be explored for cancer intervention.
表皮生长因子受体在细胞迁移和癌症转移中发挥重要作用，但其中的分子机制尚不完全清楚。我们在此表明，张力蛋白 3（tensin3）和羧基末端张力蛋白样蛋白（cten）对Deleted in liver cancer 1（DLC1）的 Ras 同源物 GTP 酶激活蛋白（Rho-GAP）活性的差异调节控制着 EGF 驱动的细胞迁移和转化。张力蛋白 3通过其肌动蛋白结合结构域与 DLC1 结合，而 cten 缺失了该结构域，从而释放了 DLC1 中 sterile alpha motif 和 Rho-GAP 结构域之间的自动抑制相互作用。因此，张力蛋白 3而不是 cten 促进了 DLC1 的激活，这反过来又导致 RhoA 的失活和细胞迁移减少。内源性张力蛋白 3的缺失而非 cten 的缺失增加了肌动蛋白应力纤维和黏着斑的形成，并增强了细胞迁移能力。然而，这些作用被 Rho 相关蛋白激酶抑制剂所消除。重要的是，张力蛋白 3或其肌动蛋白结合结构域对 DLC1 的激活大大降低了转化细胞的锚定非依赖性生长。因此，本研究将 EGF 通过 DLC1 对张力蛋白家族成员的动态调节与 Rho-GAP 联系起来，并表明张力蛋白-DLC1-RhoA 信号轴在肿瘤发生和癌症转移中发挥重要作用，并且可能被用于癌症干预的探索。
