Caenorhabditis elegans SMA-10/LRIG is a conserved transmembrane protein that enhances bone morphogenetic protein signaling.
Caenorhabditis elegans SMA-10/LRIG is a conserved transmembrane protein that enhances bone morphogenetic protein signaling.
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DOI：
10.1371/journal.pgen.1000963
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发表时间：
2010-05-20
期刊：
影响因子：
4.5
通讯作者：
Padgett RW
中科院分区：
文献类型：
--
作者：
Gumienny TL;Macneil L;Zimmerman CM;Wang H;Chin L;Wrana JL;Padgett RW
骨形态发生蛋白（BMP）通路控制着一系列的发育和稳态事件，并且必须对其自身进行精确控制。在这里，我们确定秀丽隐杆线虫SMA-10作为BMP样受体信号传导的细胞外正调节因子。SMA-10在配体DBL-1与其受体SMA-6和SMA-4之间的BMP样（Sma/Mab）途径中起遗传作用。我们克隆了SMA-10，并表明它有15个富含亮氨酸的重复序列和3个免疫球蛋白样结构域，这是跨膜蛋白LRIG亚家族的标志。SMA-10在下皮中是必需的，其中核心Sma/Mab信号传导组分起作用。我们通过用果蝇直系同源物lambik拯救SMA-10（lf）动物来证明LRIG的功能保守性，表明SMA-10物理结合DBL-1受体SMA-6和SMA-4并增强体外信号传导。这种相互作用在进化上是保守的，由LRIG 1与脊椎动物受体的结合证明。我们提出了LRIG家族成员的新作用：通过结合I型和II型受体来积极调节BMP信号传导。骨形态发生蛋白（BMP）家族成员是一种分泌型小分子信号分子，在发育和体内平衡中发挥着不同的作用。不受控制的BMP信号传导导致多种病症和疾病。BMP通过两种受体类型向接收细胞发出信号，这两种受体类型共同作用以在细胞内传播BMP信号。为了了解BMP信号是如何控制的，我们使用线虫秀丽隐杆线虫来鉴定BMP信号的保守调节子。在这里，我们的特点SMA-10，第一个细胞外的正调节DBL-1/BMP受体介导的信号。SMA-10是富含亮氨酸重复序列和免疫球蛋白样结构域（LRIG）家族的新成员。SMA-10物理结合两种类型的DBL-1/BMP受体。我们证明了LRIG功能的保守性，表明果蝇LRIG可以在功能上替代C。elegans SMA-10/LRIG、C. SMA-10可直接促进哺乳动物细胞内BMP信号传导，哺乳动物LRIG 1与BMP受体相互作用。我们的工作通过结合两种类型的BMP受体建立了LRIGs在BMP调节中的作用。
Bone morphogenetic protein (BMP) pathways control an array of developmental and homeostatic events, and must themselves be exquisitely controlled. Here, we identify Caenorhabditis elegans SMA-10 as a positive extracellular regulator of BMP–like receptor signaling. SMA-10 acts genetically in a BMP–like (Sma/Mab) pathway between the ligand DBL-1 and its receptors SMA-6 and DAF-4. We cloned sma-10 and show that it has fifteen leucine-rich repeats and three immunoglobulin-like domains, hallmarks of an LRIG subfamily of transmembrane proteins. SMA-10 is required in the hypodermis, where the core Sma/Mab signaling components function. We demonstrate functional conservation of LRIGs by rescuing sma-10(lf) animals with the Drosophila ortholog lambik, showing that SMA-10 physically binds the DBL-1 receptors SMA-6 and DAF-4 and enhances signaling in vitro. This interaction is evolutionarily conserved, evidenced by LRIG1 binding to vertebrate receptors. We propose a new role for LRIG family members: the positive regulation of BMP signaling by binding both Type I and Type II receptors. Bone morphogenetic protein (BMP) family members, small secreted signaling molecules, play diverse roles in development and homeostasis. Uncontrolled BMP signaling results in a variety of disorders and diseases. BMPs signal to receiving cells through two receptor types, which act together to propagate the BMP signal within cells. To understand how BMP signaling is controlled, we used the nematode Caenorhabditis elegans to identify conserved regulators of BMP signaling. Here, we characterize SMA-10, the first extracellular positive regulator of DBL-1/BMP receptor-mediated signaling. SMA-10 is a new member of a family with leucine rich repeats and immunoglobulin-like domains (LRIG). SMA-10 physically binds the two types of DBL-1/BMP receptor. We demonstrate conservation of LRIG function by showing that a Drosophila melanogaster LRIG can functionally substitute for loss of C. elegans SMA-10/LRIG, that C. elegans SMA-10 can directly promote mammalian BMP signaling in cells, and that mammalian LRIG1 interacts with BMP receptors. Our work establishes a role for LRIGs in BMP regulation through binding both types of BMP receptor.
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