MT1-MMP cleaves Dll1 to negatively regulate Notch signalling to maintain normal B-cell development
MT1-MMP cleaves Dll1 to negatively regulate Notch signalling to maintain normal B-cell development
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DOI：
10.1038/emboj.2011.136
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发表时间：
2011-06-01
期刊：
影响因子：
11.4
通讯作者：
Zhou, Zhongjun
中科院分区：
文献类型：
--
作者：
Jin, Guoxiang;Zhang, Fengju;Zhou, Zhongjun
Notch信号传导控制造血祖细胞（HPC）的分化。在这里，我们表明，膜1型基质金属蛋白酶（MT 1-MMP，MMP 14），在骨髓基质细胞（BMSC）中表达的细胞表面蛋白酶的损失，增加了缺口信号在HPC和特别损害B淋巴细胞的发展。当与BMSCs体外共培养时，HPC向B淋巴细胞的分化在MT 1-MMP缺陷的BMSCs上显著受损，并且这种缺陷可以被特异性Notch信号传导抑制剂DAPT完全挽救。缺陷的B淋巴细胞发育也可以在很大程度上被DAPT在体内挽救。MT 1-MMP与Notch配体Delta-like 1（Dll 1）相互作用并促进其在BMSCs细胞表面的切割。异位MT 1-MMP切割Dll 1并导致共培养细胞中Notch信号传导减少。此外，重组MT 1-MMP在细胞表面上与MT 1-MMP切割Dill相同的位点切割合成的Dll 1肽。我们的数据表明，MT 1-MMP直接切割骨髓基质细胞上的Dill，负调节Notch信号传导，以特异性地维持骨髓中正常的B细胞发育。The EMBO Journal（2011）30，2281-2293. doi：10.1038/daj.2011.136; 2011年5月13日在线发布
Notch signalling controls the differentiation of haematopoietic progenitor cells (HPCs). Here, we show that loss of membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP14), a cell surface protease expressed in bone marrow stromal cells (BMSCs), increases Notch signalling in HPCs and specifically impairs B-lymphocyte development. When co-cultured with BMSCs in vitro, HPCs differentiation towards B lymphocytes is significantly compromised on MT1-MMP-deficient BMSCs and this defect could be completely rescued by DAPT, a specific Notch signalling inhibitor. The defective B-lymphocyte development could also be largely rescued by DAPT in vivo. MT1-MMP interacts with Notch ligand Delta-like 1 (Dll1) and promotes its cleavage on cell surface in BMSCs. Ectopic MT1-MMP cleaves Dll1 and results in diminished Notch signalling in co-cultured cells. In addition, recombinant MT1-MMP cleaves a synthetic Dll1 peptide at the same site where MT1-MMP cleaves Dill on the cell surface. Our data suggest that MT1-MMP directly cleaves Dill on BMSCs to negatively regulate Notch signalling to specifically maintain normal B-cell development in bone marrow. The EMBO Journal (2011) 30, 2281-2293. doi:10.1038/emboj.2011.136; Published online 13 May 2011