由國際分子專家組成的科研小組發(fā)現(xiàn)了一個細胞信息交流的新機制,。這項關(guān)于細胞行為的新發(fā)現(xiàn)或能有助于開發(fā)新的藥物用于對抗癌癥,，風(fēng)濕性關(guān)節(jié)炎和老年癡呆癥等,。
人解整合素樣金屬蛋白酶10（ADAM10）,，其競爭對象形狀的改變將開啟細胞交流過程,。ADAM10能夠分解蛋白，由于其重要的分子機制所以改變可能會引起嚴(yán)重的疾病,。此外,，細胞間的交流過程形成了某些疾病發(fā)展的基礎(chǔ)。這項發(fā)現(xiàn)將改變我們對細胞行為的理解以及治療藥物的設(shè)計思路,。Lackmann副教授介紹說,。
這項關(guān)于細胞交流過程的發(fā)現(xiàn)相比于先前的觀點更易于理解，并將會深刻影響未來生物醫(yī)學(xué)研究的方向,。
在實驗中,，研究人員發(fā)現(xiàn)，實際上,，信號交流系統(tǒng)比復(fù)雜的信號通路更加直接和簡單,。他們表示，該過程是這樣的：首先競爭細胞表面受體的形狀發(fā)生改變,，然后激活A(yù)DAM10蛋白酶傳遞變化并對相鄰細胞產(chǎn)生影響,。這其實是一個短暫的過程。
該研究結(jié)果發(fā)布在PLoS Biology的在線版本上,。（生物谷Bioon.com）
生物谷推薦原始出處：
PLoS Biol 7(10): e1000215. doi:10.1371/journal.pbio.1000215
Cytoplasmic Relaxation of Active Eph Controls Ephrin Shedding by ADAM10
Peter W. Janes1#, Sabine H. Wimmer-Kleikamp1,2,3#¤, Achilleas S. Frangakis2, Kane Treble1, Bettina Griesshaber1, Ola Sabet3, Markus Grabenbauer3, Alice Y. Ting4, Paul Saftig5, Philippe I. Bastiaens2,3*, Martin Lackmann1*
1 Department of Biochemistry and Molecular Biology, Monash University, Victoria, Australia, 2 European Molecular Biology Laboratory, Heidelberg, Germany, 3 Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, Germany, 4 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 5 Biochemical Institute, Christian-Albrecht-University, Kiel, Germany
Release of cell surface-bound ligands by A-Disintegrin-And-Metalloprotease (ADAM) transmembrane metalloproteases is essential for signalling by cytokine, cell adhesion, and tyrosine kinase receptors. For Eph receptor ligands, it provides the switch between cell-cell adhesion and repulsion. Ligand shedding is tightly controlled by intrinsic tyrosine kinase activity, which for Eph receptors relies on the release of an inhibitory interaction of the cytoplasmic juxtamembrane segment with the kinase domain. However, a mechanism linking kinase and sheddase activities had remained elusive. We demonstrate that it is a membrane-proximal localisation of the latent kinase domain that prevents ephrin ligand shedding in trans. Fluorescence lifetime imaging microscopy and electron tomography reveal that activation extends the Eph receptor tyrosine kinase intracellular domain away from the cell membrane into a conformation that facilitates productive association with ADAM10. Accordingly, EphA3 mutants with constitutively-released kinase domains efficiently support shedding, even when their kinase is disabled. Our data suggest that this phosphorylation-activated conformational switch of EphA3 directly controls ADAM-mediated shedding.
