Regulation Mechanisms for Activin Signaling

在本研究中，我们试图阐明激活素信号转导的分子机制，激活素信号转导是由激活素受体相互作用蛋白ARIP和卵泡抑素相关基因FLRG在细胞内或细胞外调控的。(1) ARIP2在nh_2末端有1个PDZ结构域，在cooh末端有1个leucine- zippper -like结构域。ARIP2通过PDZ结构域与TGF-β家族受体中的激活素II型受体（ActRII）特异性相互作用。ARIP2的cooh末端区域与RalBP1相互作用。有趣的是，ARIP2通过Ral/ ralbp1依赖途径调节ActRII的内吞作用。(2)我们发现rasgap结合蛋白（Dok-1）是激活素诱导小鼠B细胞凋亡的重要蛋白之一。Dok- 1作为连接丝氨酸/苏氨酸受体激酶和Smads的接头蛋白，参与激活素信号传导。(3) ALK7是一种孤儿受体丝氨酸/苏氨酸激酶，在神经元组织以及胰岛和垂体中表达。激活素B和AB比激活素a更优先激活ActRII和ALK7的受体组合。在神经元细胞和胰腺β细胞中，激活素B的反应性在很大程度上依赖于ALK7。(4)我们发现了一种与TGF-β家族成员如激活素、BMP、肌生长抑制素（GDF8）和GDF11具有结合活性的小鼠卵泡抑素样蛋白FLRG。FLRG与生长因子的结合导致其生理功能的抑制。

In this study, we attempted to elucidate molecular mechanisms for activin signal transduction which is regulated either intracellularly or extracellularly by novel protein factors, ARIP (Activin receptor interacting protein) and FLRG (Follistatin lile related gene).(1) ARIP2 has one PDZ domain in the NH_2-terminal region and one leucine-zipper-like domain in the COOH-terminal region. ARIP2 interacts specifically with activin type II receptors (ActRII) among the receptors for the TGF-β family by the PDZ domain. The COOH-terminal region of ARIP2 interacts with RalBP1. Interestingly, ARIP2 regulates endocytosis of ActRII through the Ral/RalBP1-dependent pathway.(2) We identified the rasGAP-binding protein (Dok-1) as one of essential proteins responsible for activin-induced apoptosis in mouse B cell. Dok- 1 acts as an adaptor protein linking receptor serine/threonine kinases with the Smads in activin signaling.(3) ALK7 is an orphan receptor serine/threonine kinase expressed in neuronal tissues as well as in pancreatic islets and pituitary gland. The receptor combination of ActRII and ALK7 is activated more preferentially by activins B and AB rather than Activin A. Activin B responsiveness is largely ALK7-dependent both in neuronal cells and pancreatic β cells.(4) We identified a mouse follistatin-like protein, FLRG, which has binding activity for the members of TGF-β family such as activin, BMP, myostatin (GDF8) and GDF11. The binding of FLRG to growth factors results in inhibition of their physiolosical functions.