近日加州大學洛杉磯分校強生綜合癌癥中心的研究人員在一項研究中發(fā)現(xiàn)Wnt細胞信號可以引起細胞內(nèi)膜隔絕一種在蛋白質(zhì)降解中發(fā)揮關(guān)鍵作用的酶GSK3,通過抑制GSK3的功能從而影響細胞內(nèi)大量蛋白質(zhì)的穩(wěn)定性。研究論文發(fā)表在12月23日的Cell 雜志上,。
在新研究中,,研究人員證實Wnt 信號可啟動GSK3從胞質(zhì)隔離進入多泡體,,從而與它的胞質(zhì)底物分離,,導致GSK3活性抑制,。研究人員進而通過冷免疫球蛋白顯微鏡檢查證實 GSK3隔離導致細胞內(nèi)大量的蛋白質(zhì)半衰期延長。研究結(jié)果表明多泡體是Wnt信號轉(zhuǎn)導中的必需元件,。
“新研究發(fā)現(xiàn)具有非常重要的意義,,它證實了糖原合成酶激酶3 (GSK3)的功能抑制與癌癥中某些發(fā)揮關(guān)鍵作用的蛋白質(zhì)的穩(wěn)定相關(guān) ,”論文的資深作者,、強生癌癥中心的科學家,、霍華德休斯醫(yī)學研究所研究員Edward De Robertis博士說:
“我們驚訝地發(fā)現(xiàn)細胞中大約20%的蛋白質(zhì)降解都是由GSK3啟動的,其中大量的蛋白包括β- Catenin都與癌癥發(fā)生相關(guān),。我們還知道大約85%的結(jié)腸直腸癌和其他癌癥都是由于突變激活細胞內(nèi)Wnt信號引起的,。新發(fā)現(xiàn)將有可能推動開發(fā)出新的有潛力的癌癥治療方案。”De Robertis說:“過去我們只知道Wnt信號需要抑制GSK3,,但并不清楚其具體的機制,。新研究揭示W(wǎng)nt信號可促使GSK3從細胞質(zhì)隔離到多泡體中。”
當細胞接收到Wnt信號時,,細胞啟動隔離機制抑制GSK3的功能,,導致細胞蛋白質(zhì)降解速度減慢,從而使這些蛋白質(zhì)能夠在更長的時間內(nèi)調(diào)控細胞功能,,例如促進細胞增殖,。研究人員認為這有可能是許多癌細胞中Wnt信號增高的重要原因。
“蛋白質(zhì)降解是細胞生命活動中一個非常重要的組成部分,?;蚪M中大約10%的基因都參與了蛋白質(zhì)的降解,”De Robertis說:“我們現(xiàn)在知道Wnt可影響降解蛋白質(zhì)的GSK3的功能,,從而表明Wnt是細胞內(nèi)蛋白質(zhì)穩(wěn)定的一個重要的調(diào)控因子,。”(生物谷Bioon.com)
生物谷推薦原文出處:
Cell doi:10.1016/j.cell.2010.11.034
Wnt Signaling Requires Sequestration of Glycogen Synthase Kinase 3 inside Multivesicular Endosomes
Authors
Vincent F. Taelman, Radoslaw Dobrowolski, Jean-Louis Plouhinec, Luis C. Fuentealba, Peggy P. Vorwald, Iwona Gumper, David D. Sabatini, Edward M. De Robertis
Highlights
Canonical Wnt signaling causes the sequestration of GSK3 inside endosomal vesicles
Protease protection and cryoimmuno-EM show that GSK3 is sequestered inside MVBs
The MVB-forming ESCRT components HRS/Vps27 and Vps4 are required for Wnt signaling
In pulse-chase experiments overall cellular protein half-life is prolonged by Wnt3a
Summary
Canonical Wnt signaling requires inhibition of Glycogen Synthase Kinase 3 (GSK3) activity, but the molecular mechanism by which this is achieved remains unclear. Here, we report that Wnt signaling triggers the sequestration of GSK3 from the cytosol into multivesicular bodies (MVBs), so that this enzyme becomes separated from its many cytosolic substrates. Endocytosed Wnt colocalized with GSK3 in acidic vesicles positive for endosomal markers. After Wnt addition, endogenous GSK3 activity decreased in the cytosol, and GSK3 became protected from protease treatment inside membrane-bounded organelles. Cryoimmunoelectron microscopy showed that these corresponded to MVBs. Two proteins essential for MVB formation, HRS/Vps27 and Vps4, were required for Wnt signaling. The sequestration of GSK3 extended the half-life of many other proteins in addition to β-Catenin, including an artificial Wnt-regulated reporter protein containing GSK3 phosphorylation sites. We conclude that multivesicular endosomes are essential components of the Wnt signal-transduction pathway.