ROLE OF BETAGLYCAN IN INHIBIN ANTAGONISM OF ACTIVIN

Betaglycan 在激活素抑制素拮抗作用中的作用

• 批准号: 7537246
• 负责人: WYLIE W. VALE
• 金额: $ 35.02万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537246
• 关键词: Activins; Adrenal Gland Neoplasms; Affinity; Anterior Pituitary Gland; Binding; Binding Sites; Biochemical; Biological Models; Bone Morphogenetic Proteins; Cell Line; Cell physiology; Cells; Complex; Contraceptive methods; Development; Disease; Endocrine; Follicle Stimulating Hormone; Genes; Grant; In Vitro; Inhibin-beta Subunits; Knock-out; Knockout Mice; Mass Spectrum Analysis; Mediating; Mediation; Mediator of activation protein; Membrane; Messenger RNA; Modeling; Molecular; Mus; Phenotype; Pituitary Gland; Play; Process; Production; Protein Region; Protein-Serine-Threonine Kinases; Proteins; Recombinant Inhibin A; Recruitment Activity; Regulation; Role; Signal Transduction; Surface; System; TGF beta type III receptor; Techniques; Testing; Transforming Growth Factor beta; Variant; autocrine; base; cell type; crosslink; dimer; hepatic necrosis; human INHA protein; improved; in vivo; inhibin; inhibin receptor; member; paracrine; protein expression; reagent testing; receptor; reproductive; reproductive hormone; research study; response; sertoli cell

Activins and certain BMPs are members of the TGF-beta superfamily that regulate FSH production by the anterior pituitary. They and their receptors also have diverse endocrine, paracrine, and autocrine actions throughout the reproductive, endocrine and other systems and play key roles in development and in pathophysiologic processes. Inhibins oppose some, but not all actions of activin and are crucial for survival as illustrated by the lethal phenotype of inhibin alpha null mice, which suffer gonadal and adrenal tumors and liver necrosis. To exert cellular effects, activins (beta-beta dimers) bind their type II receptor serine kinases (ActRII or ActRIIB) and then recruit the type I receptor serine kinase (ALK4) to form active complexes that initiate downstream signaling. Inhibins (alpha-beta dimers) compete with activins for binding to ActRII but the inhibin/ActRII complexes do not recruit ALK4 or promote signaling. Inhibins are potent functional antagonists of activin yet the relatively low affinity of inhibins compared to activin for ActRII was not in keeping with a simple competition model. Thus other components were sought and during the past grant period we identified betaglycan (TGF-beta type III receptor) as a high affinity inhibin binding protein (co-receptor) that facilitates inhibin binding to ActRII and, thereby, greatly increases the potency of inhibin to antagonize activin signaling. In model systems we have demonstrated that inhibin can antagonize responses to some BMPs. Under Aim I, these findings will be extended to test if inhibins antagonize the effects of BMPs on pituitary cells. We will continue to characterize the binding interactions between inhibins, betaglycan, and the type II receptors, ActRII, ActRIIB and BMPRII. We will identify the betaglycan residues and regions required for inhibin binding and will produce minimized soluble betaglycan forms that will be used for biochemical and structural (with Project II) studies. Identification of the critical interactive surfaces and regions of these proteins will facilitate efforts to devise strategies for modulating inhibin responses. Aim II proposes to block betaglycan or disrupt its expression in inhibin-responsive cell types including pituitary gonadotropes. In vitro and in vivo experiments will test the importance of betaglycan as an obligate mediator of inhibin actions. Finally, under Aim III we will search for additional inhibin co-receptors. We and others have evidence for the existence of multiple inhibin binding proteins including probable variants of betaglycan, which we propose to characterize. These studies will improve our understanding of the mechanisms of inhibin action and will help identify targets for the control of fertility and management of reproductive disorders.

激活素和某些bmp是tgf - β超家族的成员，通过垂体前叶调节FSH的产生。它们及其受体在生殖、内分泌等系统中具有多种内分泌、旁分泌和自分泌作用，在发育和病理生理过程中发挥关键作用。抑制素反对激活素的部分作用，但不是所有的作用，并且对生存至关重要，正如抑制素α缺失小鼠的致死表型所表明的那样，这些小鼠患有性腺和肾上腺肿瘤以及肝坏死。施加