2005-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/692837摘要：許多的報導都認為integrin β4 和 FAK蛋白都扮演重要的角色於腫瘤進程中。事實上，它們在細胞訊息與功能的角色具有相當密切的相似性與相關性，因而被建議這兩種蛋白可以共同的調控細胞內一些特定的訊息傳遞，進而促進腫瘤細胞的轉移。在此前題之下，我們發現FAK蛋白可以直接的與integrin β4結合。而此一交互作用乃是經由FAK蛋白的N端區域。這個發現也促使我們提出進一步的鑑認出此一交互作用最基本的氨基酸序列。基於這些鑑認出的氨基酸，同時，我們也將製造一個新的FAK突變株，其失去了與integrin β4結合的能力，以利進一步的在細胞功能與訊息傳遞上的探討研究。首先，利用這種FAK突變株我們將測試其對腫瘤細胞的入侵與附著的影響和對細胞生長與凋亡的改變。除此之外，在integrin β4專一性的活化條件下，FAK所引發的訊息傳遞也將被探討。從這些研究所得到的結果，不僅可直接的證實FAK在腫瘤演化進程的功能與角色，並可提供於乳癌轉移的治療應用。<br> Abstract: Previous studies indicated that both of integrin β4 and FAK play an important role in tumor progression. In fact, their signaling and functions in cells are similar and pretty closely associated, thereby suggested to coordinately modulating certain specific cell signal pathways to promote tumor metastasis. In agreement with this idea, we have found that FAK can bind to integrin β4 directly through its amino-acid region in vivo and in vitro. This finding prompts us to further investigate how the complex of integrin β4-FAK in mediating tumor progression. To dissection the molecular mechanism of this novel pathway, we first propose to identify the integrin β4 binding sites of FAK and to generate a FAK mutant with deficiency of interaction with integrin β4 for the further functional and signaling studies. Based on this β4 binding deficient mutant, it will facilitate to explore the effects on tumor invasion and adhesion as well as cell proliferation or apoptosis. These assays will clarify the role of FAK in an integrin β4-dependent manner. In addition, several signal transduction pathways mediated by FAK will be surveyed as well. In particular, our effort will focus on the MAPK and PI3-kinase pathways whose activities are taken place during metastasis. These results will not only highlight a direct role of FAK in tumor progression, also shed a light on the therapeutic applications in breast cancers.integrin β4FAK訊息傳遞癌轉移附著細胞生長細胞凋亡integrin β4FAKsignal transductionmetastasisadhesioncell proliferationcell apoptosis