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標題: | 線蟲插入素與受器型酪胺酸激酶促進清除死細胞 Engulfment of apoptotic cells in C. elegans is mediated by integrin and receptor tyrosine kinase |
作者: | Tsung-Yuan Hsu 徐綜遠 |
指導教授: | 吳益群 |
關鍵字: | 線蟲,插入素,受器型酪胺酸激酶,吞噬,細胞凋亡, integrin,receptor tyrosine kinase,apoptosis,engulfment,C.elegans, |
出版年 : | 2010 |
學位: | 博士 |
摘要: | 計劃性細胞死亡對多細胞生物體的發育與維持其細胞總體數目的恆定相當重要,而死細胞最終必須被吞噬細胞適時的清除以防止其釋出有害物質或引起發炎反應。吞噬細胞藉由細胞膜上的吞噬受器辨認死細胞,進而將其吞噬、分解。先前線蟲的研究顯示,吞噬受器PSR-1會傳遞訊息CED-2/CrkII-CED-5/Dock180-CED-12/ELMO複合體,而活化CED-10/Rac GTPase,促使細胞膜延展並包圍死細胞。然而在遺傳分析實驗中,psr-1突變株的吞噬作用缺失遠低於下游基因突變所造成的影響,顯示可能有其他受器作用於此吞噬路徑。藉由遺傳分析實驗,我們發現插入素 INA-1-PAT-3 與PAT-2-PAT-3以及受器型酪胺酸激酶RTK-X是吞噬受器,且INA-1與RTK-X皆經由CED-2/CrkII傳遞訊號,而與PAT-2則是作用在不同的訊息傳遞路徑。在活體研究發現,INA-1的胞外區域具有辨認死細胞的功能,可直接或間接辨識死細胞上外翻的吞噬訊號phosphatidylserine (PS),其胞內區域在體外的研究中可與非受器型酪胺酸磷酸酶SRC-1結合,而CED-2/CrkII也可與SRC-1結合。由進一步的遺傳分析我們證實INA-1作為吞噬受器,接收並傳遞吞噬訊息至SRC-1,調控下游的CED-2/CrkII-CED-5/Dock180-CED-12 /ELMO複合體,進而活化CED-10/Rac GTPase,促進細胞骨架移動吞噬死細胞。我們除了確認插入素在活體生物中可以扮演吞噬受器外,我們也提出插入素可以經由與FAK無關的訊息傳遞路徑來活化CED-2/CrkII-CED-5/Dock180-CED-12 /ELMO複合體而這個非傳統的路徑在演化上是具有保守性的。 Engulfment of apoptotic cells is important for cellular homeostasis and the development of multicellular organisms. Engulfment receptor recognizes and promotes the phagocytosis of apoptotic cells by engulfing cells. Previous studies have shown that more than one engulfment receptors act upstream of the conserved signaling module CED-2/CrkII-CED-5/Dock180-CED-12/ELMO for cell corpse removal in C. elegans, but little is known about their identities, except for PSR-1. We show that, in C. elegans, integrins INA-1-PAT-3 and PAT-2- PAT-3 and receptor tyrosine kinase RTK-X function as engulfment receptors. Genetic studies show that ina-1 and rtk-x act through ced-2, whereas pat-2 likely defines a novel engulfment pathway, distinct from the previously identified ones. The INA-1 extracellular domain is shown to bind to the surface of apoptotic cells in vivo. This binding requires phospholipid scramblase SCRM-1, which promotes the exposure of phosphatidylserine, a key “eat-me” signal in apoptotic cells. Furthermore, we identified an essential role of non-receptor tyrosine kinase SRC-1 in INA-1-mediated cell corpse removal. Finally, our genetic and biochemical data suggest that SRC-1 relays the scrm-1-dependent engulfment signal from INA-1 to the conserved motility-promoting signaling complex CED-2/CrkII-CED-5/Dock180- CED-12 /ELMO for CED-10/Rac activation, probably by interactions with CED-2 and the INA-1 cytoplasmic domain, leading to the internalization of apoptotic cells. Our findings provide evidence that integrin functions as an engulfment receptor at the whole organism level and reveal a non-conventional signaling pathway, in which SRC provides a FAK-independent linkage between integrin α and the common motility–promoting signaling module CED-2/CrkII-CED-5/Dock180- CED-12/ELMO to promote the internalization of apoptotic cells. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22506 |
全文授權: | 未授權 |
顯示於系所單位: | 分子與細胞生物學研究所 |
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