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標題: 14-3-3 zeta蛋白的胺基酸Y178對於其與Src交互作用及調控肺腺癌細胞侵襲的重要性
Amino acid Y178 of 14-3-3zeta Protein Is Crucial for Its Interaction with Src and Lung Cancer Cell Invasion
作者: 蔡欣諭
Tsai, Shin-Yu
關鍵字: 14-3-3zeta;14-3-3zeta;Src;podosome;invasion;Src;podosome;侵襲
出版社: 生物醫學研究所
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肺癌,尤其是非小細胞肺癌,是近年來具有高發生率和極高死亡率之惡性腫瘤,而癌轉移則是導致病患死亡的主因。為找尋新的癌轉移相關基因,我們以競爭性基因體核酸雜交微陣列(CGHarray)發現14-3-3zeta可能具有調控轉移的潛力,並進一步證實14-3-3zeta會引發上皮-間葉的轉變作用(epithelial - mesenchymal transition ; EMT)導致癌轉移。14-3-3zeta在許多的細胞功能調控以及癌症的進程上都扮演著重要的角色,然而其造成肺腺癌轉移的分子機制並不清楚,因此本研究的目的主要是探討14-3-3zeta促進肺癌侵襲能力的機制。首先,我們觀察到細胞大量表現14-3-3zeta會促進細胞的侵襲能力並且也會使細胞分泌出更多的MMP2。同時,我們也觀察到細胞大量表現14-3-3zeta會促進podosome ring的生成。在先前的研究中已經發現Src會增加細胞侵襲的能力,而且在高度轉移的肺癌中也會高度活化,另外Src也被發現是主要會促進podosome ring形成的蛋白之一。因此我們利用生物資訊預測,發現14-3-3zeta可能會與Src產生交互作用,進一步在免疫沉澱實驗以及GST沉澱法證實兩者間確實會有交互作用。接續,我們將可能會與Src結合的位置做點突變,結果發現將Y178突變之後可以使14-3-3zeta在這個位置的酪胺酸無法受到磷酸化,並且伴隨著14-3-3zeta與Src之間的蛋白結合能力下降,而p162/165突變則不受影響,說明14-3-3zeta第178個胺基酸位置對於與Src SH2區域結合是很重要的,因此我們在低侵襲力肺癌細胞中分別大量表現正常與不同突變株14-3-3zeta蛋白,結果發現Y178的磷酸化對於14-3-3zeta促進細胞侵襲、移動和聚落的形成相當重要。另外我們也注意到Y178突變後可以使原本受到14-3-3zeta改變的表皮塑性、肌動蛋白絲的重組以及肌動蛋白環回復成原本的型態,而細胞所分泌出的MMP2也隨之減少。綜合來說,我們認為14-3-3zeta可能會參與在由Src所調控的訊息傳遞中,而且也表示了14-3-3zeta和Src之間的交互作用對於細胞的侵襲能力扮演重要的角色。

Lung cancer, predominantly non-small-cell lung cancer (NSCLC), is the most common cause of cancer deaths worldwide, and metastasis is the major cause leading to mortality for cancer patients. To discover the novel metastasis- related genes, we used CGH array and identified a potential candidate, 14-3-3zeta, which plays a critical role in a wide variety of cellular processes and tumor progression. Moreover, our previous study indicated that 14-3-3zeta can induce EMT (epithelial-mesenchymal transition) to cause lung cancer metastasis; however, the underlying molecular mechanism is still unclear. Therefore, the objective of this study is to investigate the molecular mechanism of 14-3-3zeta protein in promotion of lung cancer invasion. First, we observed that overexpression of 14-3-3zeta enhanced cell invasive capability and MMP2 secretion from the cells. Meanwhile, 14-3-3zeta expression also facilitated the formation of podosome rings. Src is a major player in the induction of tumor invasion and its activity is increased in highly metastatic lung cancer cells. And Src is also known to regulate the formation of podosome ring. By using computer prediction, we found that 14-3-3zeta has the potential to interact with Src, and the interaction was further confirmed by co-immunoprecipitation and GST pull-down assay. In addition, we performed site-direct mutagenesis to generate the various 14-3-3zeta mutants. The results showed that Y178 mutant diminished the tyrosine-phosphorylation of 14-3-3zeta and accompanied with a decrease of the interaction between 14-3-3zeta and Src. Nevertheless, there was no difference in the p162/165 mutant. Owing to the Y178 in 14-3-3zeta is crucial for the binding of Src-SH2 domain, we introduced the various 14-3-3zeta constructs to lung cancer cells and demonstrated that Y178 phosphorylation is important for 14-3-3zeta protein to promote cell invasion, migration, and colony formation activity. We also noticed that Y178 mutant could rescue the alteration of epithelial plasticity, F-actin rearrangement, formation of F-actin ring and MMP2 secretion from the cells induced by wild type. Taken together, we presume that 14-3-3zeta may be involved in Src-mediated signaling, and suggest that the association of 14-3-3zeta with Src is important for cell invasion.
其他識別: U0005-0802201015534300
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