Expression of truncated latent TGF-β-binding protein modulates TGF-β signaling
Expression of truncated latent TGF-β-binding protein modulates TGF-β signaling
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DOI：
10.1242/jcs.02352
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发表时间：
2005-05-15
影响因子：
4
通讯作者：
Rifkin, DB
中科院分区：
文献类型：
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作者：
Mazzieri, R;Jurukovski, V;Rifkin, DB
转化生长因子-β是一种由转化生长因子-β、转化生长因子-β前肽和潜在的转化生长因子-β结合蛋白组成的非活性复合体。我们研究了潜伏的转化生长因子-β结合蛋白在调节转化生长因子-β的可用性中的作用，方法是建立表达截短形式的潜伏的转化生长因子-β结合蛋白-1的转基因小鼠，该蛋白与转化生长因子-β结合，但缺失已知的N-和C-端基质结合序列。由于转化生长因子-β是角质形成细胞增殖的抑制因子，并参与毛发周期的调控，我们在角蛋白14-启动子的控制下过表达了潜伏的转化生长因子-β结合蛋白的突变形式。转基因动物的毛发表型是由于角质形成细胞增殖减少，生长期缩短，毛发周期的退化(退化期)提前开始的。这种表型似乎是由过度活跃的转化生长因子-β引起的，因为在转基因动物皮肤中观察到pSmad2/3阳性核的数量增加。这些数据表明，潜伏的转化生长因子-β结合蛋白-1的截短形式与野生型潜伏的转化生长因子-β结合蛋白竞争结合潜伏的转化生长因子-β，导致潜伏的转化生长因子-β复合体无法在细胞外基质中被正确靶向。转化生长因子-β的错误定位导致了退变原的不适当激活和过早启动，从而说明了潜在的转化生长因子-β结合蛋白与转化生长因子-β的相互作用在潜在的转化生长因子-β的靶向和激活中的重要性，以及先前报道的对小的潜在复合体分泌的影响。
Transforming growth factor-beta is released from most cells as an inactive complex consisting of transforming growth factor-beta, the transforming growth factor-beta propeptide and the latent transforming growth factor-beta-binding protein. We studied the role of latent transforming growth factor-beta-binding protein in modulating transforming growth factor-beta availability by generating transgenic mice that express a truncated form of latent transforming growth factor-p-binding protein-1 that binds to transforming growth factor-beta but is missing the known N- and C-terminal matrix-binding sequences. As transforming growth factor-beta is an inhibitor of keratinocyte proliferation and is involved in the control of hair cycling, we overexpressed the mutated form of latent transforming growth factor-beta-binding protein under the control of the keratin 14-promoter. Transgenic animals displayed a hair phenotype due to a reduction in keratinocyte proliferation, an abbreviated growth phase and an early initiation of the involution (catagen) phase of the hair cycle. This phenotype appears to result from excess active transforming growth factor-beta, as enhanced numbers of pSmad2/3-positive nuclei are observed in transgenic animal skin. These data suggest that the truncated form of latent transforming growth factor-beta-binding protein-1 competes with wild-type latent transforming growth factor-p-binding protein for binding to latent transforming growth factor-beta, resulting in latent transforming growth factor-beta complexes that fail to be targeted correctly in the extracellular matrix. The mislocalization of the transforming growth factor-beta results in inappropriate activation and premature initiation of catagen, thereby illustrating the significance of latent transforming growth factor-beta-binding protein interaction with transforming growth factor-beta in the targeting and activation of latent transforming growth factor-beta in addition to previously reported effects on small latent complex secretion.