Qian Yong, Zhong Xiaosong, Flynn Daniel C, Zheng Jenny Z, Qiao Meng, Wu Chuanyue, Dedhar Shoukat, Shi Xianglin, Jiang Bing-Hua
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV 26506, USA.
Oncogene. 2005 Apr 28;24(19):3154-65. doi: 10.1038/sj.onc.1208525.
One of the hallmarks of integrin signaling is an increase in cell migration and invasion, both of which are associated with actin filament rearrangements. Integrin-linked kinase (ILK) is a cytoplasmic effector of integrin receptors. ILK is known to be involved in multiple cellular functions. However, the signaling pathways involved in ILK-mediated cellular structure and motility remain to be elucidated. Here, we have demonstrated that overexpression of ILK was sufficient to induce actin filament rearrangements, to form cell motility structures, and to increase cell migration and invasion in a phosphatidylinositol 3-kinase (PI3K)-dependent manner. This corresponds with the activation of both Akt and p70 ribosomal protein S6 kinase (p70S6K1). Overexpression of dominant-negative mutants of Akt inhibited ILK-dependent activation of p70S6K1, indicating that Akt is upstream of p70S6K1 in response to ILK signaling. Overexpression of ILK was sufficient to induce Rac1 activation, which was abolish by a PI3K inhibitor, indicating that Rac1 activity is involved in ILK signaling in a PI3K dependent manner. Inhibition of Akt, Rac1, or p70S6K1 inhibited the effects of ILK on actin filaments and cell migration, suggesting a regulatory role of the PI3K/Akt/p70S6K1/Rac1 signaling pathway in response to ILK signaling. We have shown that overexpression of a dominant-negative ILK was sufficient to abolish fibronectin peptide (PHSRN)-induced rearrangements of actin filaments and cell migration and invasion. Taken together, our results identify a mechanism through which ILK can regulate both integrin-associated rearrangements of actin filaments and cell migration and invasion at the integrin receptor-proximal region.
整合素信号传导的一个标志是细胞迁移和侵袭增加，这两者都与肌动蛋白丝重排有关。整合素连接激酶（ILK）是整合素受体的一种细胞质效应器。已知ILK参与多种细胞功能。然而，ILK介导的细胞结构和运动性所涉及的信号通路仍有待阐明。在此，我们已经证明，ILK的过表达足以诱导肌动蛋白丝重排，形成细胞运动结构，并以磷脂酰肌醇3激酶（PI3K）依赖的方式增加细胞迁移和侵袭。这与Akt和p70核糖体蛋白S6激酶（p70S6K1）的激活相对应。Akt显性负突变体的过表达抑制了ILK依赖的p70S6K1激活，表明在响应ILK信号时，Akt在p70S6K1的上游。ILK的过表达足以诱导Rac1激活，而PI3K抑制剂可消除这种激活，表明Rac1活性以PI3K依赖的方式参与ILK信号传导。抑制Akt、Rac1或p70S6K1可抑制ILK对肌动蛋白丝和细胞迁移的作用，提示PI3K/Akt/p70S6K1/Rac1信号通路在响应ILK信号时具有调节作用。我们已经表明，显性负ILK的过表达足以消除纤连蛋白肽（PHSRN）诱导的肌动蛋白丝重排以及细胞迁移和侵袭。综上所述，我们的结果确定了一种机制，通过该机制ILK可以在整合素受体近端区域调节整合素相关的肌动蛋白丝重排以及细胞迁移和侵袭。
