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Membrane-type 1 Matrix Metalloproteinase Modulates Tissue Homeostasis by a Non-proteolytic Mechanism
iScience ( IF 5.8 ) Pub Date : 2020-11-10 , DOI: 10.1016/j.isci.2020.101789
Mukundan Attur 1 , Cuijie Lu 1 , Xiaodong Zhang 2 , Tianzhen Han 1 , Cassidy Alexandre 2 , Cristina Valacca 2 , Shuai Zheng 2 , Sarina Meikle 2 , Branka Brukner Dabovic 3 , Evelyne Tassone 2 , Qing Yang 1 , Victoria Kolupaeva 4 , Shoshana Yakar 5 , Steven Abramson 1 , Paolo Mignatti 1, 2, 3
Affiliation  

Membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP-14), a transmembrane proteinase with a short cytoplasmic tail, is a major effector of extracellular matrix remodeling. Genetic silencing of MT1-MMP in mouse (Mmp14−/−) and man causes dwarfism, osteopenia, arthritis, and lipodystrophy, abnormalities ascribed to defective collagen turnover. We have previously shown non-proteolytic functions of MT1-MMP mediated by its cytoplasmic tail, where the unique tyrosine (Y573) controls intracellular signaling. The Y573D mutation blocks TIMP-2/MT1-MMP-induced Erk1/2 and Akt signaling without affecting proteolytic activity. Here, we report that a mouse with the MT1-MMP Y573D mutation (Mmp14Y573D/Y573D) shows abnormalities similar to but also different from those of Mmp14−/− mice. Skeletal stem cells (SSC) of Mmp14Y573D/Y573D mice show defective differentiation consistent with the mouse phenotype, which is rescued by wild-type SSC transplant. These results provide the first in vivo demonstration that MT1-MMP modulates bone, cartilage, and fat homeostasis by controlling SSC differentiation through a mechanism independent of proteolysis.



中文翻译:

膜 1 型基质金属蛋白酶通过非蛋白水解机制调节组织稳态

膜 1 型基质金属蛋白酶 (MT1-MMP, MMP-14) 是一种具有短细胞质尾的跨膜蛋白酶,是细胞外基质重塑的主要效应物。MT1-MMP 在小鼠 ( Mmp14 -/- ) 和人类中的基因沉默会导致侏儒症、骨质减少、关节炎和脂肪营养不良,这些异常归因于胶原蛋白更新缺陷。我们之前已经展示了由其细胞质尾部介导的 MT1-MMP 的非蛋白水解功能,其中独特的酪氨酸 (Y573) 控制细胞内信号传导。Y573D 突变阻断 TIMP-2/MT1-MMP 诱导的 Erk1/2 和 Akt 信号传导,而不影响蛋白水解活性。在这里,我们报告了具有 MT1-MMP Y573D 突变 ( Mmp14 Y573D/Y573D ) 的小鼠显示出与Mmp14 -/-小鼠。Mmp14 Y573D/Y573D小鼠的骨骼干细胞 (SSC)显示出与小鼠表型一致的分化缺陷,这通过野生型 SSC 移植得以挽救。这些结果首次在体内证明 MT1-MMP 通过独立于蛋白水解的机制控制 SSC 分化来调节骨、软骨和脂肪稳态。

更新日期:2020-11-25
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