Signaling by MuSK, a component of the Agrin receptor

MuSK（Agrin 受体的一个组成部分）发出的信号

• 批准号: 7676367
• 负责人: Steven Burden
• 金额: $ 4万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676367
• 关键词: Ache; Adaptor Signaling Protein; Agrin; Amyotrophic Lateral Sclerosis; Antibodies; Binding; Binding Sites; Birth; Chromosome Pairing; Complex; Congenital Myasthenic Syndromes; Defect; Disease; Exhibits; Failure; Family; Genes; Glare; Human; Individual; Lead; Ligands; Low Density Lipoprotein Receptor; Mediating; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle-Specific Kinase; Mutant Strains Mice; Mutation; Myasthenia Gravis; Myasthenic Syndrome; Myocardium; Nerve; Neurodegenerative Disorders; Neuromuscular Diseases; PTB Domain; Pathway interactions; Patients; Phosphorylation; Postsynaptic Membrane; Proteins; Public Health; Recruitment Activity; Signal Pathway; Signal Transduction; Skeletal system; Synapses; Tyrosine; Tyrosine Phosphorylation; Work; adapter protein; agrin receptor; clinically relevant; congenital neuromuscular disorder; design; member; mutant; novel therapeutics; peripheral membrane protein 43K; postsynaptic; presynaptic; programs; research study; scaffold; synaptogenesis

DESCRIPTION (provided by applicant): Our failure to understand how Agrin stimulates MuSK tyrosine phosphorylation is perhaps the most fundamental and glaring gap in our understanding of signaling at the neuromuscular synapse. We found that Lrp4, a member of the LDL receptor family, is essential for Agrin to stimulate MuSK tyrosine phosphorylation, suggesting that Lrp4 is a key component of an Agrin receptor complex and potentially the long-sought receptor for Agrin. The experiments described here are designed to determine whether Lrp4 binds Agrin and/or MuSK and how Lrp4 mediates Agrin responsiveness and synaptic differentiation. How MuSK, once activated, stimulates postsynaptic differentiation is similarly poorly understood. Dok-7 has recently been identified as an adaptor protein, which is recruited to tyrosine phosphorylated MuSK and which is essential for synaptic differentiation. Further, mutations in Dok-7 are a major cause of neuromuscular disorders, termed congenital myasthenic syndromes (CMS). The experiments described here are designed to identify and study the proteins that are recruited to Dok-7, which will be critical to understand how Dok-7 regulates synaptic differentiation and how mutations in Dok-7 cause CMS. The proposed studies are clinically relevant for several reasons. First, mutations in Dok-7 cause CMS, so understanding how Dok-7 works will contribute to a better understanding of this disease and may lead to novel therapeutic strategies. Second, mutations in genes that are downstream from Dok-7 may likewise cause CMS, so identifying the pathway downstream from Dok-7 is likewise important. Third, because mutations in other synaptic genes (e.g. AChR subunits, rapsyn, MuSK, AChE) also cause CMS, mutations that interfere with the function of Lrp4 selectively in muscle may also be responsible for CMS. Finally, because 20% of patients with myasthenia gravis are sero- negative for auto-antibodies to AChR or MuSK, these individuals presumably carry auto-antibodies to other synaptic proteins, possibly Lrp4. PUBLIC HEALTH RELEVANCE: The formation of neuromuscular synapses requires a complex exchange of signals between motor neurons and developing muscle fibers leading to the formation of a highly specialized postsynaptic membrane and a highly differentiated nerve terminal. The signals and mechanisms responsible for this complex differentiation program are poorly understood but require the neurally-derived ligand, Agrin, and the receptor tyrosine kinase, MuSK. Defects in this signaling pathway are responsible for a variety of congenital neuromuscular disorders and could underlie or contribute to neurodegenerative diseases such as ALS. The experiments described here are designed to determine how Lrp4 and Dok-7, two newly discovered components of this signaling pathway mediate Agrin responsiveness, lead to MuSK phosphorylation and stimulate synaptic differentiation.

描述（由申请人提供）：我们未能理解Agrin如何刺激麝香酪氨酸磷酸化可能是我们理解神经肌肉突触信号的最根本和最明显的差距。我们发现LRP4是LDL受体家族的成员，对于Agrin刺激Musk酪氨酸磷酸化至关重要，这表明LRP4是Agrin受体复合物的关键组成部分，并且可能是Agrin的长期受体。此处描述的实验旨在确定LRP4是否结合Agrin和/或Musk以及LRP4如何介导Agrin的反应性和突触分化。一旦激活的麝香如何刺激突触后分化的理解较少。 DOK-7最近被确定为衔接蛋白，该蛋白被募集到酪氨酸磷酸化的麝香中，这对于突触分化至关重要。此外，DOK-7中的突变是神经肌肉疾病的主要原因，称为先天肌关系综合征（CMS）。此处描述的实验旨在识别和研究募集到DOK-7的蛋白质，这对于了解DOK-7如何调节突触分化以及DOK-7中的突变如何引起CMS至关重要。拟议的研究在临床上具有多种原因。首先，DOK-7中的突变会导致CMS，因此了解DOK-7的工作方式将有助于更好地理解该疾病，并可能导致新的治疗策略。其次，从DOK-7下游的基因突变也可能引起CMS，因此鉴定DOK-7下游的途径同样重要。第三，因为其他突触基因的突变（例如ACHR亚基，Rapsyn，Musk，Ache）也会引起CMS，因此有选择地干扰LRP4在肌肉中的功能的突变也可能负责CMS。最后，由于20％的肌无力重症患者对ACHR或MUSK的自身抗体是血清阴性的，因此这些个体大概可以将自身抗体携带到其他突触蛋白，可能是LRP4。公共卫生相关性：神经肌肉突触的形成需要运动神经元之间复杂的信号交换和发展肌肉纤维，从而形成了高度专业的突触后膜和高度分化的神经终末。负责此复杂分化程序的信号和机制知之甚少，但需要神经衍生的配体Agrin和受体酪氨酸激酶Musk。该信号通路中的缺陷负责各种先天性神经肌肉疾病，可能是ALS等神经退行性疾病的基础或有助于神经退行性疾病。此处描述的实验旨在确定LRP4和DOK-7（该信号通路的两个新发现的组成部分）如何介导Agrin的反应性，导致麝香磷酸化并刺激突触分化。