DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism.
DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism.
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DOI：
10.1158/0008-5472.can-10-2158
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Zimonjic DB
中科院分区：
文献类型：
--
作者：
Yang X;Popescu NC;Zimonjic DB
DLC 1基因编码一种Rho GTP酶激活蛋白（RhoGAP），在几种常见的人类癌症中起肿瘤抑制作用。DLC 1的多结构域结构使其能够与许多其他蛋白质相互作用。在这里，我们报告说，促炎蛋白S100 A10（也称为p11），一个关键的细胞表面受体纤溶酶原调节细胞周围蛋白水解和肿瘤细胞的侵袭，是一个新的结合伙伴DLC 1在人类细胞。我们确定这两种蛋白质共定位在细胞质中，它们的结合是由DLC 1的中心结构域和S100 A10的C-末端的中心序列介导的。由于相同的S100 A10序列也介导与膜联蛋白2的结合，我们发现DLC 1与膜联蛋白2竞争与S100 A10的相互作用。DLC 1与S100 A10的结合并不影响DLC 1的RhoGAP活性，但它通过将S100 A10从膜联蛋白2中置换出来并使其易于被泛素依赖性降解，从而以剂量依赖性方式降低了S100 A10表达的稳态水平。这一过程减弱了纤溶酶原活化，并导致体外细胞迁移、侵袭、集落形成和侵袭性肺癌细胞的锚定非依赖性生长的抑制。这些结果表明，一种新的GAP非依赖性机制有助于DLC 1的肿瘤抑制活性，并突出了在某些癌症中涉及DLC 1的蛋白质-蛋白质相互作用的重要性和复杂性。
The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the pro-inflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the two proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to annexin 2, we found that DLC1 competed with annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1’s RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein-protein interactions involving DLC1 in certain cancers.