Betaglycan inhibits TGF-β signaling by preventing type I-type II receptor complex formation -: Glycosaminoglycan modifications alter betaglycan function
Betaglycan inhibits TGF-β signaling by preventing type I-type II receptor complex formation -: Glycosaminoglycan modifications alter betaglycan function
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DOI：
10.1074/jbc.m105110200
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发表时间：
2002-01-04
影响因子：
4.8
通讯作者：
Wells, RG
中科院分区：
文献类型：
--
作者：
Eickelberg, O;Centrella, M;Wells, RG
转化生长因子 (TGF)-β 是一种多功能生长因子，在发育、细胞增殖和基质沉积中发挥重要作用。它通过顺序激活两种丝氨酸/苏氨酸激酶受体（I 型和 11 型受体）发出信号。第三种细胞表面受体，β聚糖，在某些细胞类型中充当 TGF-β 的共同受体，增强 TGF-β 介导的信号传导。我们检查了缺乏内源性β聚糖的肾上皮LLC-PK1细胞中β聚糖的功能。我们通过报告基因表达、胸苷掺入、胶原蛋白产生以及下游信号效应器 Smad2 和 Smad3 的磷酸化来测量，证明 LLC-PK1 细胞中 β 聚糖的表达会抑制 TGF-β 信号传导。相比之下，L6成肌细胞中β聚糖的表达增强了TGF-β信号传导，这与已发表的文献一致。 β聚糖在LLC-PK1细胞中的作用不是通过配体隔离或可溶性受体产生的增加来介导的，据报道，可溶性受体可作为配体拮抗剂。相反，我们证明，与 L6 细胞不同，在 LLC-PK1 细胞中，β 聚糖的表达会阻止 I 型和 11 型 TGF-β 受体之间的关联，而这是信号传导所必需的。这是β聚糖的糖胺聚糖修饰的功能。 LLC-PK1 细胞中的 β 聚糖表现出比 L6 细胞中更高分子量的糖胺聚糖 (GAG) 链，并且 GAG(-) β 聚糖突变体不会抑制 LLC-PK1 细胞中的 TGF-β 信号传导或 I 型/II 型受体关联。我们的数据表明，β聚糖可以通过一种新的机制作为TGF-β信号传导的有效抑制剂，并为蛋白聚糖共受体在生长因子信号传导中的重要但复杂的作用提供支持。
Transforming growth factor (TGF)-beta is a multifunctional growth factor with important roles in development, cell proliferation, and matrix deposition. It signals through the sequential activation of two serine/threonine kinase receptors, the type I and type 11 receptors. A third cell surface receptor, betaglycan, serves as a co-receptor for TGF-beta in some cell types, enhancing TGF-beta-mediated signaling. We have examined the function of betaglycan in renal epithelial LLC-PK1 cells that lack endogenous betaglycan. We demonstrate that the expression of betaglycan in LLC-PK1 cells results in inhibition of TGF-beta signaling as measured by reporter gene expression, thymidine incorporation, collagen production, and phosphorylation of the downstream signaling effectors Smad2 and Smad3. In comparison, the expression of betaglycan in L6 myoblasts enhances TGF-beta signaling, which is consistent with the published literature. The effects of betaglycan in LLC-PK1 cells are not mediated by ligand sequestration or increased production of a soluble form of the receptor, which has been reported to serve as a ligand antagonist. We demonstrate instead that in LLC-PK1 cells, unlike L6 cells, expression of betaglycan prevents association between the type I and type 11 TGF-beta receptors, which is required for signaling. This is a function of the glycosaminoglycan modifications of betaglycan. Betaglycan in LLC-PK1 cells exhibits higher molecular weight glycosaminoglycan (GAG) chains than in L6 cells, and a GAG(-) betaglycan mutant does not inhibit TGF-beta signaling or type I/type II receptor association in LLC-PK1 cells. Our data indicate that betaglycan can function as a potent inhibitor of TGF-beta signaling by a novel mechanism and provide support for an essential but complex role for proteoglycan co-receptors in growth factor signaling.