The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways
The mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathways
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DOI：
10.1074/jbc.m102750200
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发表时间：
2002-02-15
影响因子：
4.8
通讯作者：
Knaus, P
中科院分区：
文献类型：
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作者：
Nohe, A;Hassel, S;Knaus, P
骨形态发生蛋白（BMPs）是调节细胞生长、分化和凋亡的多功能蛋白。BMP-2信号通过两种受体（BRI和BRIT）在细胞表面以同质和异质复合物的形式表达。在配体结合之前，在预形成的异聚物中发现了低但可测量的bmp受体水平。大部分受体只有在配体加入后才被招募到异寡聚复合物中。为此，BMP-2首先结合高亲和力受体BRI，然后将BRII招募到信号复合体中。然而，由BRII和BRI组成的预形成复合物仍然需要配体结合，这表明它可能介导激活构象变化。使用几种方法，我们解决了以下问题：(i)在缺乏BMP-2的情况下，预制复合物是否不能发出信号？BRII受体的哪些结构域对这种复合物的形成至关重要？（iii） bmp诱导的与预形成的受体复合物发送的信号是否存在差异？通过测量Smads、p38 MAPK和碱性磷酸酶的激活，我们发现激酶缺陷型BRII受体突变体抑制BMP信号传导的能力取决于它们与BRI形成异质复合物的能力。重要的是，BRII突变体不能形成预组装受体复合物，但可以加入bmp诱导的受体复合物，这不会干扰Smad途径，但会抑制碱性磷酸酶的诱导以及p38磷酸化。这些结果表明，BMP-2与预形成的受体复合物结合所诱导的信号激活了Smad途径，而BMP-2诱导的受体募集激活了一个不同的、不依赖于Smad的途径，通过p38 MAPK诱导碱性磷酸酶活性。
Bone morphogenetic proteins (BMPs) are multifunctional proteins regulating cell growth, differentiation, and apoptosis. BMP-2 signals via two types of receptors (BRI and BRIT) that are expressed at the cell surface as homomeric as well as heteromeric complexes. Prior to ligand binding, a low but measurable level of BMP-receptors is found in preformed hetero-oligomeric complexes. The major fraction of the receptors is recruited into hetero-oligomeric complexes only after ligand addition. For this, BMP-2 binds first to the high affinity receptor BRI and then recruits BRII into the signaling complex. However, ligand binding to the preformed complex composed of BRII and BRI is still required for signaling, suggesting that it may mediate activating conformational changes. Using several approaches we have addressed the following questions: (i) Are preformed complexes incompetent of signaling in the absence of BMP-2? (ii) Which domains of the BRII receptors are essential for this complex formation? (iii) Are there differences in signals sent from BMP-induced versus preformed receptor complexes? By measuring the activation of Smads, of p38 MAPK and of alkaline phosphatase, we show that the ability of kinase-deficient BRII receptor mutants to inhibit BMP signaling depends on their ability to form heteromeric complexes with BRI. Importantly, a BRII mutant that is incapable in forming preassembled receptor complexes but recruits into a BMP-induced receptor complex does not interfere with the Smad pathway but does inhibit the induction of alkaline phosphatase as well as p38 phosphorylation. These results indicate that signals induced by binding of BMP-2 to preformed receptor complexes activate the Smad pathway, whereas BMP-2-induced recruitment of receptors activates a different, Smad-independent pathway resulting in the induction of alkaline phosphatase activity via p38 MAPK.