Intracellular and extracellular control of activin signaling by novel regulatory molecules

活化素是转化生长因子（transforming growth factor，TGF-β）家族的成员，在红系分化、骨生长、中胚层诱导等生物学系统中发挥着重要作用。活化素II型受体（Activin type II receptor，ActRIIs）是将活化素信号传递到细胞内信号通路的主要受体。激活素与ActRII的结合募集激活素I型受体并启动下游信号传导。我们已经发现PDZ蛋白，命名为激活素受体相互作用蛋白（ARIPs），特异性地与ActRIIs结合。我们研究了ARIPs调控ActRIIs细胞表面表达和细胞定位的机制。ARIP 2通过不同的结构域与ActRII和RalBP 1（Ral结合蛋白1）相互作用，以显著改变ActRII的定位。ARIP 2的过表达增强ActRII的内吞作用。这些结果表明ARIP 2是一个新的调节细胞表面ActRII表达和激活素功能的因子，并鉴定了一个新的激活素结合蛋白-卵泡抑素相关基因（FLRG）。FLRG蛋白以高亲和力结合激活素和肌肉生长抑制素。FLRG的生物学活性与卵泡抑素相似，但两者的调控和表达模式不同。免疫组织化学分析显示FLRG分布于睾丸生精细胞、肾小管、肺上皮细胞和心肌。因此，尽管结构和功能相似，卵泡抑素和FLRG可能在体内作为激活素/GDF结合蛋白发挥不同的作用。

Activins, members of the transforming growth factor (TGF-β) family have various effects on diverse biologic systems, such as erythroid differentiation, bone growth, mesoderm induction, etc.Activin type II receptors (ActRIIs) are the primary receptors that transmit the activin signal to intracellular signaling pathways. Binding of activins to ActRIIs recruits the activin type I receptor and initiates downstream signaling. We have found that PDZ proteins, named activin receptor-interacting proteins (ARIPs), specifically associate with ActRIIs. We have studied the mechanism that ARIPs regulate cell surface expression and cellular localization of ActRIIs. ARIP2 interacts with both ActRIIs and RalBP1 (Ral binding protein 1) through different domains to dramatically change the localization of ActRIIs. Overexpression of ARIP2 enhances endocytosis of ActRIIs. These data indicate that ARIP2 is a novel factor regulating cell surface ActRII expression and activin function.A novel activin binding protein, follistatin-related gene (FLRG) was identified. FLRG protein binds activin and myostatin with a high affinity. The biological activity of FLRG is similar to those of follistatin, however, the regulation and expression patterns of follistatin and FLRG differ. Immunohistochemical analysis shows that FLRG is distributed in spermatogenic cells of the testis, renal tubules, epithelial cells of the lung, and myocardium. Thus, although structurally and functionally similar, follistatin and FLRG likely play distinct roles as activin/GDF binding proteins in vivo.