Gumienny Tina L, MacNeil Lesley T, Wang Huang, de Bono Mario, Wrana Jeffrey L, Padgett Richard W
Waksman Institute, Department of Molecular Biology and Biochemistry, Cancer Institute of New Jersey, Rutgers University, Piscataway, New Jersey 08854, USA.
Curr Biol. 2007 Jan 23;17(2):159-64. doi: 10.1016/j.cub.2006.11.065.
Bone morphogenetic protein (BMP) pathways are required for a wide variety of developmental and homeostatic decisions, and mutations in signaling components are associated with several diseases. An important aspect of BMP control is the extracellular regulation of these pathways. We show that LON-2 negatively regulates a BMP-like signaling pathway that controls body length in C. elegans. lon-2 acts genetically upstream of the BMP-like gene dbl-1, and loss of lon-2 function results in animals that are longer than normal. LON-2 is a conserved member of the glypican family of heparan sulfate proteoglycans, a family with several members known to regulate growth-factor signaling in many organisms. LON-2 is functionally conserved because the Drosophila glypican gene dally rescues the lon-2(lf) body-size defect. We show that the LON-2 protein binds BMP2 in vitro, and a mutant variation of LON-2 found in lon-2(e2140) animals diminishes this interaction. We propose that LON-2 binding to DBL-1 negatively regulates this pathway in C. elegans by attenuating ligand-receptor interactions. This is the first report of a glypican directly interacting with a growth-factor pathway in C. elegans and provides a mechanistic model for glypican regulation of growth-factor pathways.
骨形态发生蛋白（BMP）信号通路参与多种发育和稳态调控过程，信号通路组分的突变与多种疾病相关。BMP信号调控的一个重要方面是其细胞外调节机制。我们发现LON-2负向调控一种类似BMP的信号通路，该通路控制秀丽隐杆线虫的体长。lon-2在功能上位于类BMP基因dbl-1的上游，lon-2功能缺失会导致线虫体长超过正常水平。LON-2是硫酸乙酰肝素蛋白聚糖糖基磷脂酰肌醇锚定蛋白家族的保守成员，该家族的多个成员在许多生物体中参与生长因子信号调控。LON-2在功能上具有保守性，因为果蝇的糖基磷脂酰肌醇锚定蛋白基因dally能够挽救lon-2(lf)突变体的体型缺陷。我们发现LON-2蛋白在体外能够结合BMP2，并且在lon-2(e2140)突变体中发现的LON-2突变体变体减弱了这种相互作用。我们推测LON-2与DBL-1的结合通过减弱配体-受体相互作用负向调控秀丽隐杆线虫中的这一信号通路。这是关于糖基磷脂酰肌醇锚定蛋白直接与秀丽隐杆线虫生长因子信号通路相互作用的首次报道，并为糖基磷脂酰肌醇锚定蛋白调控生长因子信号通路提供了一个机制模型。
