National Tsing Hua University Institutional Repository:c-Cbl-mediated Protease-activated Receptor 1-induced Degradation of Src
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    NTHUR > College of Life Sciences  > Life Sciences > LIFE Conference Papers >  c-Cbl-mediated Protease-activated Receptor 1-induced Degradation of Src

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    Title: c-Cbl-mediated Protease-activated Receptor 1-induced Degradation of Src
    Other Titles: 泛素黏合酶 c-Cbl 參與蛋白酶激活接受器一所引起酪氨酸蛋白激酶Src的降解
    Authors: Lee, P-Y.;Fu, H-W.
    Teacher: 傅化文
    Date: 2007
    Publisher: 中華民國毒物學學會;台灣生物化學及分子生物學學會;中華民國細胞及分子生物學學會;中華民國臨床生化學會;中國生理學會;台灣藥理學會;中華民國解剖學學會
    Relation: The Twenty-Second Joint Annual Conference of Biomedical Sciences, Taipei, Taiwan, MAR 2006
    Keywords: PAR1
    Abstract: Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor for thrombin. In addition to active Src by G protein, PAR1 recruits Src by ?-arrestin to transduce signals. Src is then sorted to lysosomes with the activated PAR1 for degradation. However, the mechanism by which PAR1-induced degradation of Src and the receptor itself is still unclear. It has been reported that degradation of active Src is mediated by c-Cbl, an ubiquitin E3 ligase. To determine whether c-Cbl mediates the degradation of Src and PAR1 after receptor activation, CHO-K1 cells stably expressing FLAG-tagged PAR1 were transiently transfected with a dominant negative c-Cbl mutant to examine its effect on the degradation of Src and PAR1. I found that stimulation of PAR1 induced degradation of Src. The degradation of Src was blocked by chloroquine, a lysosomal inhibitor. The dominant negative c-Cbl mutant lacking the RING-finger domain (?RF c-Cbl) inhibited PAR1-induced degradation of Src and partially inhibited the degradation of PAR1. However, ?RF c-Cbl did not affect the endocytosis of PAR1. Taken together, these results indicated that c-Cbl mediated lysosomal degradation of Src and PAR1 after the receptor activation.
    蛋白酶激活接受器一 (protease-activated receptor 1, PAR1) 是一個被凝血蛋白酶 (thrombin) 所激活的G蛋白連結接受器(G protein-coupled receptor)。酪氨酸蛋白激酶Src 除了會被連接G蛋白的蛋白酶激活接受器一活化外,還會藉由-制動素 (-arrestin) 結合到蛋白酶激活接受器一進而傳遞此接受器的下游訊號。接著酪氨酸蛋白激酶Src會和活化的蛋白酶激活接受器一結合並一起到溶酶體 (lysosome) 降解。然而,蛋白酶激活接受器一所引起的酪氨酸蛋白激酶Src及此接受器被降解的機制仍然不清楚。有研究文獻指出,泛素黏合酶c-Cbl (ubiquitin E3 ligase c-Cbl) 會參與活化的酪氨酸蛋白激酶Src降解反應。為了探討在蛋白酶激活接受器一活化後,泛素黏合酶c-Cbl是否會參與酪氨酸蛋白激酶Src及此接受器的降解反應,我將有穩定表現FLAG標幟之蛋白酶激活接受器一的中國倉鼠卵巢細胞 (CHO-K1) 短暫表現優勢陰性型突變 (dominant negative) 的泛素黏合酶c-Cbl,並且測試此突變的泛素黏合酶c-Cbl對於蛋白酶激活接受器一所引起酪氨酸蛋白激酶Src降解反應的影響。我發現溶酶體抑制劑—氯化喹啉 (chloroquine) 會抑制蛋白酶激活接受器一活化所引起的酪氨酸蛋白激酶Src及此接受器的降解。又此缺少環指狀功能區域 (RING-finger domain) 之優勢陰性突變的泛素黏合酶c-Cbl (RF c-Cbl) 會完全抑制蛋白酶激活接受器一引起的酪氨酸蛋白激酶Src降解,且只會部分抑制蛋白酶激活接受器一的降解。然而,此缺少環指狀功能區域之優勢陰性突變的泛素黏合酶c-Cbl卻完全不影響蛋白酶激活接受器一的胞飲作用。綜合上述結果可知,在蛋白酶激活接受器一被活化後,泛素黏合酶c-Cbl參與酪氨酸蛋白激酶Src及蛋白酶激活接受器一的降解。
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    Appears in Collections:[Institute of Molecular and Cellular Biology] MCBLIFE Conference Papers
    [ Life Sciences] LIFE Conference Papers

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