Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9
Bone morphogenetic protein receptor type II is a receptor for growth differentiation factor-9
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DOI：
10.1095/biolreprod67.2.473
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发表时间：
2002-08-01
影响因子：
3.6
通讯作者：
Hsueh, AJW
中科院分区：
文献类型：
--
作者：
Vitt, UA;Mazerbourg, S;Hsueh, AJW
生长分化因子-9（GDF-9）是由卵母细胞分泌的一种糖蛋白，能够刺激颗粒细胞增殖并抑制分化。GDF-9是已知通过I型和II型丝氨酸/苏氨酸激酶受体发出信号的配体的转化生长因子β超家族的成员。在测序的人类基因组中，已经鉴定了七种I型和六种II型受体。基于系统发育和序列分析，我们预测GDF-9可能与已知的I型和II型受体相互作用。我们获得了可溶性嵌合蛋白与融合的Fc部分的候选受体的胞外域的免疫球蛋白，并测试其作为功能性拮抗剂的能力。添加骨形态发生蛋白受体II型（BMPRII）胞外域在阻断GDF-9刺激颗粒细胞增殖和GDF-9抑制FSH刺激的孕酮产生方面最有效。此外，骨形态发生蛋白受体IA型、骨形态发生蛋白受体IB型和激活素受体IIA型的胞外域在阻断GDF-9作用方面部分有效。此外，BMPRII胞外域在共沉淀研究中直接与GDF-9相互作用，证明了BMPRII胞外域作为GDF-9的结合蛋白的作用。为了证明BMPRII在卵泡细胞中GDF-9信号传导中的作用，使用特定的BMPRII反义寡聚体在培养的颗粒细胞中阻断该蛋白的表达。BMPRII生物合成的抑制完全阻止了GDF-9诱导颗粒细胞胸苷掺入。GDF-9的表达是必不可少的早期卵泡发育，和II型和I型受体的存在下，在新生大鼠卵巢进行了验证，通过逆转录聚合酶链反应。这些结果表明BMPRII在小窦卵泡颗粒细胞中介导GDF-9作用的重要作用，并表明GDF-9的作用可能通过与BMPRII和一种或多种I型受体结合来转导。
Growth differentiation factor-9 (GDF-9) is a glycoprotein secreted by the oocyte that is capable of stimulating granulosa cell proliferation and inhibiting differentiation. GDF-9 is a member of the transforming growth factor beta superfamily of ligands known to signal through type I and II serine/threonine kinase receptors. In the sequenced human genome, seven type I and six type II receptors have been identified. Based on phylogenetic and sequence analyses, we predicted that GDF-9 likely interacts with known type I and type II receptors. We obtained soluble chimeric proteins with the ectodomains of candidate receptors fused to the Fc portion of immunoglobin and tested their ability to act as functional antagonists. Addition of bone morphogenetic protein receptor type II (BMPRII) ectodomain was most effective in blocking GDF-9 stimulation of granulosa cell proliferation and GDF-9 suppression of FSH-stimulated progesterone production. In addition, the ectodomains of bone morphogenetic protein receptor type IA, bone morphogenetic protein receptor type IB, and activin receptor type IIA were partially effective in blocking GDF-9 action. Furthermore, the BMPRII ectodomain directly interacted with GDF-9 in a coprecipitation study demonstrating the role of the BMPRII ectodomain as a binding protein for GDF-9. To demonstrate the role of BMPRII in GDF-9 signaling in follicular cells, the expression of this protein was blocked in cultured granulosa cells using specific BMPRII antisense oligomers. Inhibition of BMPRII biosynthesis completely prevented the GDF-9 induction of granulosa cell thymidine incorporation. GDF-9 expression is essential for early follicle development, and the presence of the type II and type I receptors in the neonatal rat ovary was verified by reverse transcription polymerase chain reaction. These results demonstrate the important role of BMPRII in mediating GDF-9 action in granulosa cells from small antral follicles and indicate that the effects of GDF-9 might be transduced by binding to BMPRII and one or more type I receptors.