Homophilic interactions of tetraspanin CD151 up-regulate motility and matrix metalloproteinase-9 expression of human melanoma cells through adhesion-dependent c-Jun activation signaling pathways
Homophilic interactions of tetraspanin CD151 up-regulate motility and matrix metalloproteinase-9 expression of human melanoma cells through adhesion-dependent c-Jun activation signaling pathways
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DOI：
10.1074/jbc.m601209200
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发表时间：
2006-08-25
影响因子：
4.8
通讯作者：
Lee, Hansoo
中科院分区：
文献类型：
--
作者：
Hong, In-Kee;Jin, Young-June;Lee, Hansoo
四联蛋白膜蛋白CD151被认为通过启动信号事件来调节肿瘤的侵袭和转移。参与这一调控的cd151介导的信号通路仍有待揭示。在这项研究中，我们发现将CD151稳定转染到缺乏CD151表达的MelJuSo人黑色素瘤细胞中，可显著提高细胞活力、基质金属蛋白酶-9 （MMP-9）表达和侵袭性。CD151过表达对细胞运动和MMP-9表达的增强作用被靶向focal adhesion kinase （FAK）、Src、p38 MAPK和JNK的抑制剂和小干扰rna所抵消，这表明这些信号成分在CD151信号通路中发挥了重要作用。此外，CD151诱导的MMP-9表达是通过c-Jun结合MMP-9基因启动子AP-1位点介导的，表明AP-1是通过CD151信号通路激活的。同时，在MelJuSo细胞中发现CD151与α (3) β(1)和α (6) β(1)整合素相关，相关整合素的激活是CD151刺激MMP-9表达和FAK、Src、p38 MAPK、JNK和c-Jun激活的先决条件。此外，一个细胞上的CD151被证明与表达CD151的邻近细胞结合，这表明CD151是一种亲同性相互作用蛋白。CD151的亲同性相互作用增加了转染CD151的MelJuSo细胞的运动性和MMP-9的表达，以及FAK-、Src-、p38 MAPK-和jnk介导的c-Jun以粘附依赖的方式激活。此外，内源性CD151的C8161黑色素瘤细胞也显示出对亲同型CD151相互作用的响应，以诱导FAK， Src和c-Jun的粘附依赖性激活。这些结果表明，在人类黑色素瘤细胞中，CD151的亲同性相互作用通过FAK- Src- MAPKs通路刺激整合素依赖的c-Jun信号传导，导致细胞运动和MMP-9表达增强。
The tetraspanin membrane protein CD151 has been suggested to regulate cancer invasion and metastasis by initiating signaling events. The CD151-mediated signaling pathways involved in this regulation remain to be revealed. In this study, we found that stable transfection of CD151 into MelJuSo human melanoma cells lacking CD151 expression significantly increased cell motility, matrix metalloproteinase-9 ( MMP-9) expression, and invasiveness. The enhancement of cell motility and MMP-9 expression by CD151 overexpression was abrogated by inhibitors and small interfering RNAs targeted to focal adhesion kinase ( FAK), Src, p38 MAPK, and JNK, suggesting an essential role of these signaling components in CD151 signaling pathways. Also, CD151-induced MMP-9 expression was shown to be mediated by c-Jun binding to AP-1 sites in the MMP-9 gene promoter, indicating AP-1 activation by CD151 signaling pathways. Meanwhile, CD151 was found to be associated with alpha(3)beta(1) and alpha(6)beta(1) integrins in MelJuSo cells, and activation of associated integrins was a prerequisite for CD151-stimulated MMP-9 expression and activation of FAK, Src, p38 MAPK, JNK, and c-Jun. Furthermore, CD151 on one cell was shown to bind to neighboring cells expressing CD151, suggesting that CD151 is a homophilic interacting protein. The homophilic interactions of CD151 increased motility and MMP-9 expression of CD151-transfected MelJuSo cells, along with FAK-, Src-, p38 MAPK-, and JNK-mediated activation of c-Jun in an adhesion-dependent manner. Furthermore, C8161 melanoma cells with endogenous CD151 were also shown to respond to homophilic CD151 interactions for the induction of adhesion-dependent activation of FAK, Src, and c-Jun. These results suggest that homophilic interactions of CD151 stimulate integrin-dependent signaling to c-Jun through FAK- Src- MAPKs pathways in human melanoma cells, leading to enhanced cell motility and MMP-9 expression.