REGULATION OF TRANSFORMING GROWTH-FACTOR-BETA ACTIVATION BY DISCRETE SEQUENCES OF THROMBOSPONDIN-1
REGULATION OF TRANSFORMING GROWTH-FACTOR-BETA ACTIVATION BY DISCRETE SEQUENCES OF THROMBOSPONDIN-1
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DOI：
10.1074/jbc.270.13.7304
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发表时间：
1995-03-31
影响因子：
4.8
通讯作者：
MURPHYULLRICH, JE
中科院分区：
文献类型：
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作者：
SCHULTZCHERRY, S;CHEN, H;MURPHYULLRICH, JE
转化生长因子-β(TGF-β)是一种强大的生长调节蛋白，几乎所有细胞都能以潜伏的形式分泌。调节转化生长因子-β活性的一个主要机制是通过将潜伏期的过程集中到分子的生物活性形式的因子来实现的。我们以前已经证明，血小板α颗粒和细胞外基质蛋白血栓反应蛋白1(TSP1)通过一种不依赖于细胞的蛋白酶机制激活潜伏的转化生长因子-β，并将转化生长因子-β结合/激活区域定位于血小板TSP1的1型重复序列。我们现在报道，重组人TSP1，而不是重组小鼠TSP2，激活了潜在的转化生长因子-β。通过使用合成肽，进一步将激活定位于TSP1的第一和第二类型1重复之间的唯一序列RFK(氨基酸412-415)。具有TSP2中相应序列的多肽RLR没有活性。此外，基于TSP1和TSP2的类型1重复序列的六肽GGWSHW抑制了TSP1对潜在的转化生长因子-β的激活。该多肽与I-125激活的转化生长因子-β结合，并抑制TSP1与潜伏的转化生长因子-β的相互作用。TSP2也抑制了TSP1对潜在的转化生长因子-β的激活，推测是通过WSHW序列与转化生长因子-β竞争性结合。这些研究表明，潜在的转化生长因子-β的激活是由TSP1的1型重复序列中存在的两个序列介导的，一个序列(GGWSHW)与活性的转化生长因子-β结合并潜在地定向TSP分子，另一个序列(RFK)激活潜在的转化生长因子-β。基于这些位点的多肽在调节转化生长因子-β的激活方面具有潜在的治疗应用。
Transforming growth factor-beta (TGF-beta) is a potent growth regulatory protein secreted by virtually all cells in a latent form. A major mechanism of regulating TGF-beta activity occurs through factors that central the process ing of the latent to the biologically active form of the molecule. We have shown previously that thrombospondin 1 (TSP1), a platelet alpha-granule and extracellular matrix protein, activates latent TGF-beta via a protease and cell-independent mechanism and have localized the TGF-beta binding/activation region to the type 1 repeats of platelet TSP1. We now report that recombinant human TSP1, but not recombinant mouse TSP2, activates latent TGF-beta. Activation was further localized to the unique sequence RFK found between the first and the second type 1 repeats of TSP1 (amino acids 412-415) by the use of synthetic peptides. A peptide with the corresponding sequence in TSP2, RLR, was inactive. In addition, a hexapeptide GGWSHW, based on a sequence present in the type 1 repeats of both TSP1 and TSP2, inhibited the activation of latent TGF-beta by TSP1. This peptide bound to I-125-active TGF-beta and inhibited interactions of TSP1 with latent TGF-beta. TSP2 also inhibited activation of latent TGF-beta by TSP1, presumably by competitively binding to TGF-beta through the WSHW sequence. These studies show that activation of latent TGF-beta is mediated by two sequences present in the type 1 repeats of TSP1, a sequence (GGWSHW) that binds active TGF-beta and potentially orients the TSP molecule and a second sequence (RFK) that activates latent TGF-beta. Peptides based on these sites have potential therapeutic applications for modulation of TGF-beta activation.