Abl為一種非受體的酪氨酸蛋白激脢，通常藉由聯結蛋白而與其受質結合，進而在不同的生理刺激下調控各種功能，包括細胞骨架的重整、細胞生長、及細胞凋亡。Abi蛋白家族最早是因為此蛋白質會與Abl互相結合而被發現並分離出來，其功能可能跟調控致癌型Abl所引起的細胞轉型及癌化能力有關。在本篇論文中，我們利用酵母菌雙雜交法篩選Abi的結合蛋白，並鑑定出Cdc2是一個新穎的Abi結合蛋白。在本研究中我們想探討Abi在連結Abl和Cdc2的關係中所扮演的角色。我們發現這三者能在果蠅及哺乳類動物細胞中以複合體形式存在，在細胞中大量表現Abi時能加強Abl 與Cdc2間的結合，顯示Abi是一聯結蛋白，藉此連結來增強Abl 和Cdc2的交互作用。另外，Abi能促進Abl磷酸化Cdc2的第十五個氨基酸 (Y15)，並導致Cdc2活性的減弱。我們也發現在果蠅細胞同時表現Abl 及Abi能抑制細胞生長。更進一步，在帶有Bcr-Abl (癌化型Abl) 基因的細胞中，若利用STI571抑制Bcr-Abl的激脢活性或是以RNA干擾術來降低Bcr-Abl蛋白質的生成時，這種細胞在游離輻射的處理下所引起Cdc2 Y15的磷酸化程度及G2-M細胞週期的停滯程度會降低。如此的結果指出，Bcr-Abl可能直接或間接藉由Abi蛋白質的連結來調控DNA傷害所引起Cdc2磷酸化及其活性的抑制。但是，在非Bcr-Abl的細胞中，c-Abl似乎在調控Cdc2及細胞週期上只扮演一小部分的功能。此外，由於Abl 及Abi都已知在肌動蛋白絲的重組上扮演功能，因而我們也探討Cdc2在細胞中的位置並發現Cdc2會位在富含肌動蛋白絲的lamellipodia上，並且和Abl 、Abi同時位在相類似的細胞結構上。總結來說，我們認為DNA傷害所導致Cdc2活性在Bcr-Abl細胞中受到抑制，以及Cdc2在肌動蛋白絲的重組過程中移動至lamellipodia之機制可能與Abl及Abi有關聯。

Abl is a non-receptor tyrosine kinase, which is frequently coupled by adaptor proteins to interact with its substrates for the regulation of cytoskeleton rearrangement, cell growth, and apoptosis in response to a variety of biological stimuli. The Abl-interactor (Abi) family members were first reported as Abl adaptors involved in the regulation of oncogenic Abl transforming activity. In the present study, we have used a yeast two-hybrid screen to identify Cdc2 as a novel Abi-binding protein. This finding led us to investigate the role of Abi in linking Abl and Cdc2. These three proteins formed tri-complex in Drosophila and mammalian cells. Expressing Abi in cells greatly enhanced the formation of Abl-Cdc2 complex, suggesting Abi functions as an adaptor protein facilitating the binding between Abl and Cdc2. We showed that Abi promoted Abl-mediated phosphorylation of Cdc2 at tyrosine 15 and inactivation of kinase activity of Cdc2. Coexpression of Abl and Abi in Drosophila S2 cells led to suppression of cell growth. Furthermore, we showed that Bcr-Abl-positive cells exhibited abrogated radiation-induced Cdc2-Y15 phosphorylation and G2-M arrest as Bcr-Abl kinase activity was blocked by STI571 or protein expression was suppressed by siRNA. This result is consistent with the fact that inhibitory phosphorylation at Y15 of Cdc2 triggers the G2-M arrest in response to DNA damage. Nonetheless, in Bcr-Abl-negative cells, c-Abl appears to be redundant in modulating Cdc2 for checkpoint control. Since both Abl and Abi are also involved in actin dynamics, we investigated the subcellular localization of Cdc2 and, surprisingly, found that it was recruited to the lamellipodia, colocalizing with Abl and Abi in actin-rich bundles. Together, the data suggest that inhibition of Cdc2 kinase for G2-M DNA damage checkpoint in Bcr-Abl cells and the recruitment of Cdc2 to lamellipodia for actin dynamics are associated with Abl and Abi proteins.

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