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Title: | Grb7參與在細胞移動與腫瘤進程之訊息調控 Signal Transduction of Grb7 in Cell Migration and Tumor Progression |
Authors: | Pei-Yu Chu 朱珮瑜 |
Advisor: | 沈湯龍(Tang-Long Shen) |
Keyword: | Grb7,FAK,表皮生長因子,乳癌,非小細胞肺癌,癌症治療藥物, Grb7,FAK,EGF,breast cancer,non-small-cell-lung-cancer,cancer therapy, |
Publication Year : | 2012 |
Degree: | 博士 |
Abstract: | Growth factor receptor bound protein-7 (Grb7) 是一個有數個功能區域 (domain) 的銜接蛋白 (adaptor protein),能與許多訊息分子產生交互作用並藉此調控細胞功能。我們首先確認了上游激酶 focal adhesion kinase (FAK) 磷酸化Grb7的位置 (Tyr188 和 Tyr 338)。當這些位置被突變,Grb7便無法被磷酸化也不能影響下游如 paxillin 及 ERK1/2 的磷酸化。此外,在 integrin 的訊息傳遞鏈中,FAK和Grb7會結合形成複合物,進而有效影響癌細胞的移動,複製,與不須附著的生長能力。我們進一步發現在 erbB2 及 Grb7 共同大量表現的乳癌細胞株中,當受到表皮生長因子 (EGF) 的刺激,Grb7 會被磷酸化,接著與 Ras-GTPase 產生結合後促進其活性,並影響下游ERK1/2之磷酸化。這條 EGFR-Grb7-Ras- ERK1/2 訊息傳導鏈能提高乳癌細胞的生長能力,進而促進癌化現象。另外,我們在非小細胞肺癌細胞中同樣發現 Grb7會受到 EGF 刺激而磷酸化。在此系統中,Grb7 能透過調控轉錄因子 STAT3 的活性來影響 EphA4 基因表現。EphA4 能和 EGFR 交互作用,產生互相磷酸化與活化的現象,並因此增強 EGFR 的下游訊息傳遞。因此,在 EGFR-Grb7-STAT3-EphA4 的訊息傳遞下,細胞的生長,移動,侵染 (invasion) 與腫瘤進程 (tumor progression) 都受到調控。我們的研究提供了一個對 Grb7參與之訊息傳遞有更多了解的機會。基於眾多證據直指 Grb7 在許多癌症中皆扮演著重要角色,我們的實驗結果也突顯出未來針對 Grb7 發展疾病偵測標誌及標靶治療的可能性。 Growth factor receptor bound protein-7 (Grb7) is a multi-domain adaptor protein which is regulated cell functions by interacting with signaling molecules to transmit signal transduction. We first demonstrate that FAK was capable of phosphorylating the Tyr-188 and Tyr-338 within Grb7, and the tyrosine phosphorylation-deficient mutants evidently altered the phosphorylation of paxillin and ERK1/2 but less on AKT, implying their involvement in the FAK•Grb7-mediated cellular functions. Additionally, the formation of FAK-Grb7 complexes and Grb7 phosphorylation by FAK in an integrin-dependent manner were essential for cell migration, proliferation and anchorage-independent growth in A431 cells, indicating the importance of FAK-Grb7 complexes in tumorigenesis. We further show that Grb7 promotes tumorigenesis through the formation of a novel EGFR-Grb7-Ras signaling complex. Grb7-mediated cell proliferation and growth are essential for the tumorigenesis in erbB2-Grb7-overexpressing SK-Br3 breast cancer cells. EGF-induced de novo Grb7 tyrosine phosphorylation recruits and activates Ras-GTPases and subsequently promotes the phosphorylation of ERK1/2, thereby stimulating tumor growth. We also reveal a novel mechanism by which Grb7 regulates cell migration, proliferation, invasion and tumorigenesis of A549 NSCLC cells through the EGF-triggered EGFR-Grb7-STAT3-EphA4 signaling pathway. Our data provide a better understanding on the signal transduction event for Grb7-mediated cellular functions. Grb7 might have the potential to develop as a prognostic biomarker model and improve the overall sensitivity and specificity of cancer therapies. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/64986 |
Fulltext Rights: | 有償授權 |
Appears in Collections: | 植物病理與微生物學系 |
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ntu-101-1.pdf Restricted Access | 4.33 MB | Adobe PDF |
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