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研究生:郭權益
研究生(外文):Chuan-Yi
論文名稱:ZAK調控cbl結合到ArgBP2
論文名稱(外文):ZAK regulates the binding of cbl to ArgBP2
指導教授:楊肇基楊肇基引用關係
指導教授(外文):Jaw-Ji Yang
學位類別:碩士
校院名稱:中山醫學大學
系所名稱:口腔醫學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
畢業學年度:93
語文別:中文
論文頁數:54
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ZAK包括一個 kinase domain,leucine zipper(LZ)以及一個sterile-alpha motif(SAM)domain,是屬於MAP kinase kinase kinase(MAP3K)。ZAK 已證實是經由下游基因MKK7來間接活化JNK/SAPK這條路徑,進而影響到細胞生長停滯(arrest)。ZAK藉由yeast-two hybrid system找到了與ZAK相關的蛋白,找到與調節actin cytoskeleton有關的ArgBP2。ArgBP2是具有一個SoHo(Sorbin Homology)domain 及三個src homology 3 domain的蛋白質。ArgBP2功能類似一種adapter protein在stress fiber裡扮演收集訊息的集合體,也可有效的連結Abl family kinase及actin cytoskeleton。此外ArgBP2也存在於Z-disks推測與心臟的收縮舒張有關聯性,或許在Z-disks裡是扮演著訊息傳遞的載體。
實驗中利用ZAK結構上的三大功能區,分別是kinase domain,leucine zipper(LZ)及一個sterile-alpha motif(SAM)domain來觀察蛋白質間的交互作用。經由共同免疫沉澱實驗發現ZAK與ArgBP2有鍵結交互作用關係。利用ZAK在三大功能區的變異來觀察與ArgBP2個關係,發現可能在leucine zipper與ArgBP2有交互作用,應該扮演決定性的角色。然而在訊息傳遞的研究中,常利用點突變產生dominant-negative 變異株如:ZAK-DN 及constitutively-active變異株如:ZAK-E/E 的方式探討未知的功能,因此實驗中利用ZAK點突變株、ZAK各功能區缺失、ArgBP2各功能區缺失的變異株,來探討ZAK的訊息傳遞路徑與相對應負責的功能區相關性。結果發現ZAK 、ZAK-E/E、ZAKΔSAM可以造成ArgBP2的磷酸化。Cbl是一種E3-ubiquitin ligase,實驗中利用Cbl來觀察ArgBP2與ZAK之間的相關性。發現在ZAK使ArgBP2產生磷酸化時會減少Cbl,相反的,在ZAK-DN情況下ArgBP2沒有磷酸化反應時Cbl會增加。利用ArgBP2的各功能區缺失來實驗與ZAK間的鍵結關係。
ZAK contains a kinase domain,a leucine-zipper(LZ) and a sterile-alpha motif(SAM) domain,which belongs to the MAP kinase kinase kinase(MAP3K),and could activate the JNK/SAPK pathway through MKK7 in the mammalian cells. Expression of ZAK but not kinase-dead ZAK in 10T1/2 cells results in the disruption of actin stress fibers and morphological changes. Expression of wild-type ZAK increases the cell population in the G2/M phase of the cell cycle, which may indicate G2 arrest.By yeast two hybrid system to identify a ZAK-associated protein with ArgBP2. ArgBP2 has a SoHo(Sorbin Homology) domain and three src homology 3 domain,and plays an important role in actin cytoskeleton. Arg and c-Abl represent the mammalian members of the Abelson family of protein-tyrosine kinases. ArgBP2 functions as an adapter protein to assemble signaling complexes in stress fibers, which potentially links between Abl family kinases and the actin cytoskeleton. In addition, the localization of ArgBP2 to Z-disks suggests that ArgBP2 may influence the contractile or elastic properties of cardiac sarcomeres and that the Z-disk is a target of signal transduction cascades.
We use the immunoprecipitation and western blot analysis to study the interaction between ZAK and ArgBP2.ZAK uses leucine-zipper domain to bind ArgBP2.We obsvered ZAK phosphorylates ArgBP2. Cbl is an E3-ubquitin ligase, we use Cbl to observe the interaction between ArgBP2. We suggested that phosphorylated forms of ArgBP2 might decrease its ability to bind Cbl.The ZAK-ArgBP2-Cbl signalling is not associated NF-κB activation.
目錄 2
中文摘要 4
英文摘要 6
壹、前言 8
貳、研究動機 14
參、實驗材料 15
肆、實驗方法 26
伍、實驗結果 33
陸、討論 37
柒、參考文獻 40
圖次 44
附錄文次 54
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