Distinct transforming growth factor-beta (TGF-beta) receptor subsets as determinants of cellular responsiveness to three TGF-beta isoforms.
Distinct transforming growth factor-beta (TGF-beta) receptor subsets as determinants of cellular responsiveness to three TGF-beta isoforms.
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发表时间：
1990-11
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通讯作者：
S. Cheifetz;H. Hernandez;M. Laiho;P. Dijke;K. Iwata;J. Massagué
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作者：
S. Cheifetz;H. Hernandez;M. Laiho;P. Dijke;K. Iwata;J. Massagué
对三种哺乳动物转化生长因子-β1、β2和β3亚型的鉴定表明，作为Mv1Lu水貂肺上皮细胞系的生长抑制因子，转化生长因子-β3比转化生长因子-β1和转化生长因子-β2更有效(ED50=0.5 pm比2 pm)。然而，在胎牛心脏内皮细胞系(FBHE)中，转化生长因子-β1和转化生长因子-β3的效力至少是生长抑制因子转化生长因子-β2的50倍，转化生长因子-β2是一种非常弱的生长抑制因子(ED50大于或等于0.5 nm)。因此，作为生长抑制因子，转化生长因子-β1和-β3比转化生长因子-β2更相似。在FBHE细胞检测中，血清α2-巨球蛋白的存在降低了转化生长因子-βS的生物学效力，尤其是转化生长因子-β2。然而，α2-巨球蛋白的这种作用不足以解释细胞对转化生长因子-β2的低反应性。对转化生长因子-β受体作为细胞对转化生长因子-β亚型特异性反应性决定因素的评价表明，转化生长因子-β1、-β2和-β3对膜蛋白多糖有相似的亲和力。然而，它们与I型和II型受体结合的能力不同，I型和II型受体与转化生长因子-β信号转导有关。转化生长因子-β1与转化生长因子-β3相似，尽管不完全相同，但在与所有被测细胞系中的所有受体I和II结合方面，比转化生长因子-β2作为竞争对手要强得多。已在Mv1Lu细胞中鉴定出一组受体I和II，它与转化生长因子-β2具有高亲和力(Kd约为10 pm)，并以在Mv1Lu细胞中具有生物活性的浓度与该因子结合。在FBHE细胞中不能检测到这个受体亚群，这表明转化生长因子-β2受体高亲和力水平的细胞特异性差异可能导致细胞特异性对该异构体的反应差异。因此，尽管它们在结构和生物学上相似，但转化生长因子-β1、-β2和-β3与受体结合的能力不同，这种结合方式与它们作为生长抑制物的效力相关。
Characterization of the three mammalian transforming growth factor-beta (TGF-beta) isoforms, TGF-beta 1, -beta 2, and -beta 3, indicates that TGF-beta 3 is somewhat more potent (ED50 = 0.5 pM versus 2 pM) than TGF-beta 1 and TGF-beta 2 as a growth inhibitor of the Mv1Lu mink lung epithelial cell line. In the fetal bovine heart endothelial (FBHE) cell line, however, TGF-beta 1 and -beta 3 are at least 50-fold more potent than TGF-beta 2 which is a very weak growth inhibitor (ED50 greater than or equal to 0.5 nM). Thus, as growth inhibitors, TGF-beta 1 and -beta 3 resemble each other more than TGF-beta 2. The presence of serum alpha 2-macroglobulin in the FBHE cell assays decreases the biological potency of TGF-beta s, in particular TGF-beta 2. This effect of alpha 2-macroglobulin, however, is not sufficient to explain the low responsiveness of FBHE cells to TGF-beta 2. Evaluation of the role of TGF-beta receptors as determinants of cell-specific responsiveness to TGF-beta isoforms indicates that TGF-beta 1, -beta 2, and -beta 3 have similar affinity for the membrane proteoglycan, betaglycan. They differ, however, in their ability to bind to receptor types I and II which are implicated in TGF-beta signal transduction. TGF-beta 1 is similar, albeit not identical, to TGF-beta 3 and much more potent than TGF-beta 2 as a competitor for binding to the overall population of receptors I and II in all cell lines tested. A subset of receptors I and II has been identified in Mv1Lu cells which has high affinity for TGF-beta 2 (KD approximately 10 pM) and binds this factor at concentrations that are biologically active in Mv1Lu cells. This receptor subset could not be detected in FBHE cells, suggesting that cell-specific differences in the level of high affinity of TGF-beta 2 receptors may lead to cell-specific differences in responsiveness to this isoform. Thus, despite their structural and biological similarities, TGF-beta 1, -beta 2, and -beta 3 diverge in their ability to bind to receptors in a manner that correlates with their potency as growth inhibitors.