Interaction of deleted in liver cancer 1 with tensin2 in Caveolae and implications in tumor suppression
Interaction of deleted in liver cancer 1 with tensin2 in Caveolae and implications in tumor suppression
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DOI：
10.1158/0008-5472.can-05-2850
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发表时间：
2006-09-01
期刊：
影响因子：
11.2
通讯作者：
Ng, Irene Oi-Lin
中科院分区：
文献类型：
--
作者：
Yam, Judy Wai Ping;Ko, Frankie Chi Fat;Ng, Irene Oi-Lin
肝癌缺失基因1(DLC1)是新近发现的一种在肝细胞癌中低表达的抑癌基因。DLC1编码一个Rho GTPase激活蛋白结构域，该结构域在肝癌细胞细小颗粒中显示出生长抑制活性。我们最近的发现表明，DLC1抑制Rho介导的肌动蛋白应激纤维的形成与其生长抑制活性有关。在本研究中，我们将tensin2确定为DLC1的新结合伙伴。Tensin2属于一个新的粘着斑蛋白家族，在细胞骨架组织和信号转导中发挥关键作用。张力蛋白的失调此前已被认为与人类癌症有关。Tensin2在人肝脏中高表达。将tensin2基因导入低表达的人肝癌细胞系，可显著抑制细胞生长并诱导细胞凋亡。在体内外，Tensin2与DLC1直接相互作用。这两种蛋白都定位于细胞质中的点状结构。DLC1和tensin2的序列分析表明，这两种蛋白都含有小窝蛋白-1结合基序。体内免疫沉淀研究证实，这两种蛋白确实与内源性小窝蛋白-1相互作用，小窝蛋白-1是小窝的主要结构成分。我们的发现为DLC1在肝细胞中的作用提供了一个新的模型，在该模型中，DLC1-tensin2复合体与小窝中的Rho GTP酶相互作用，实现细胞骨架的重组。
Deleted in liver cancer 1 (DLC1) is a recently identified tumor suppressor gene frequently underexpressed in hepatocellular carcinoma (HCC). DLC1 encodes a Rho GTPase-activating protein domain that exhibits growth-suppressive activity in HCC cell fines. Our recent finding has revealed that inhibition of Rho-mediated actin stress fiber formation by DLC1 is associated with its growth inhibitory activity. In the present study, we identified tensin2 as the novel binding partner of DLC1. Tensin2 belongs to a new family of focal adhesion proteins that play key roles in cytoskeleton organization and signal transduction. Dysregulation of tensin proteins has previously been implicated in human cancers. Tensin2 is highly expressed in human liver. Introduction of tensin2 into HCC cell lines with low expression of tensin2 caused significant growth inhibition and induction of apoptosis. Tensin2 directly interacted with DLC1 in vitro and in vivo. Both proteins localized to punctate structures in the cytoplasm. Sequence analysis of DLC1 and tensin2 identified caveolin-1 binding motif in both proteins. In vivo immuno-precipitation study confirmed that both proteins indeed interacted with endogenous caveolin-1, which is the major structural component of caveolae. Our findings presented here suggest a new model for the action of DLC1 in hepatocytes, whereby DLC1-tensin2 complex interacts with Rho GTPases in caveolae to effect cytoskeletal reorganization.