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Mechanism of RIN1 Signaling in Neuronal Plasticity

RIN1 信号传导在神经元可塑性中的机制

基本信息

批准号：
7259412
负责人：
JOHN J. COLICELLI
金额：
$ 27.09万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7259412
关键词：
ABL1 gene ABL2 gene Active Sites Adaptor Signaling Protein Attention Binding Biological CRK gene CRKL gene Cells Compatible Complex Cytoskeletal Modeling Cytoskeleton Data Dendrites Dendritic Spines Disease Docking Down-Regulation Elevation Employee Strikes Family Goals Histocompatibility Testing In Vitro Knowledge Learning Localized Long-Term Potentiation Mass Spectrum Analysis Mediating Memory Mus Mutant Strains Mice N-ras Genes NRAS gene Neuronal Plasticity Neurons Neurotransmitter Receptor Pathway interactions Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Principal Investigator Property Prosencephalon Protein Tyrosine Kinase Proteins RNA Splicing Response to stimulus physiology Role Signal Pathway Signal Transduction Site Specificity Stimulus Techniques Testing Tissues Variant abl Oncogene brain tissue cell transformation cell type excitatory neuron in vivo insight mutant neuropsychiatry p21 N-Ras Protein programs protein function proto-oncogene protein c-crk response tyrosine kinase ABL1

项目摘要

DESCRIPTION (provided by applicant): The RIN1 protein is a RAS effector expressed predominantly in mature forebrain neurons. RIN1 stimulates ABL family tyrosine kinases and directs cytoskeletal remodeling. RIN1 null mutant mice show a striking increase in long term potentiation (LTP) and enhancement in memory (i.e. RIN1 normally inhibits learning). H-,K-, NRAS and ABL2 are also expressed in forebrain neurons and perform learning and memory functions. These studies provide critical insights into a tissue-specific RAS pathway that regulates neuronal plasticity (learning). Understanding RIN1 function may also have implications for neuropsychiatric disorders. RIN1 binds to ABL proteins. Moreover, RIN1 is unique as a direct ABL kinase activator. RAS appears to stimulate RIN1 activation of ABL2 and these three proteins (RAS, RIN1, ABL2) are found as a complex in vivo. These data demonstrate a physical and functional connection between RAS and ABL proteins. RIN1 promotes the ABL2 phosphorylation of CRKII and CRKL, adaptor proteins that coordinate cytoskeletal remodeling. The first aim of this proposal is to define the mechanism by which RIN1 stimulates ABL2 kinase activity. This may involve a substrate-specific enhancement (i.e. RIN1 provides a docking site for CRK proteins) or an allosteric function (i.e., RIN1 induces changes in the ABL2 kinase active site). Understanding the RIN1- mediated stimulation mechanism should expand opportunities for manipulating ABL function in learning, as well as in cell transformation. The second aim is to define signaling components used by RIN1 to promote cytoskeletal remodeling. RIN1 and ABL2 are complexed with CRKL in vivo. CRKII and CRKL reorganize the cytoskeleton through multiple SH2 and SH3 binding partners. Identification of RIN1/CRK(L) complex components will provide new insights into stimulus-induced and cell type specific remodeling. The third aim of this proposal is to evaluate the contribution of RIN1 to neuronal plasticity. RIN1 can coordinate cytoskeletal remodeling as well as compete with other RAS effectors. We will use cultured neurons and brain tissue to determine how neuronal stimulation engages the RAS-RIN1-ABL2-CRK(L) pathway and how activation of this pathway negatively regulates plasticity. Special focus will be placed on dendritic spine remodeling because the connection of this phenomenon to learning remains conjectural.

描述（由申请人提供）：RIN1 蛋白是主要在成熟前脑神经元中表达的 RAS 效应子。 RIN1 刺激 ABL 家族酪氨酸激酶并指导细胞骨架重塑。 RIN1 缺失突变小鼠的长时程增强 (LTP) 和记忆力显着增强（即 RIN1 通常会抑制学习）。 H-、K-、NRAS和ABL2也在前脑神经元中表达并执行学习和记忆功能。这些研究为调节神经元可塑性（学习）的组织特异性 RAS 通路提供了重要的见解。了解 RIN1 功能也可能对神经精神疾病产生影响。 RIN1 与 ABL 蛋白结合。此外，RIN1 作为直接 ABL 激酶激活剂是独一无二的。 RAS 似乎可以刺激 ABL2 的 RIN1 激活，并且这三种蛋白（RAS、RIN1、ABL2）在体内被发现为复合物。这些数据证明了 RAS 和 ABL 蛋白之间的物理和功能联系。 RIN1 促进 CRKII 和 CRKL（协调细胞骨架重塑的衔接蛋白）的 ABL2 磷酸化。该提案的第一个目的是确定 RIN1 刺激 ABL2 激酶活性的机制。这可能涉及底物特异性增强（即 RIN1 为 CRK 蛋白提供对接位点）或变构功能（即 RIN1 诱导 ABL2 激酶活性位点的变化）。了解 RIN1 介导的刺激机制应该会扩大在学习和细胞转化中操纵 ABL 功能的机会。第二个目标是定义 RIN1 用于促进细胞骨架重塑的信号传导成分。 RIN1 和 ABL2 在体内与 CRKL 复合。 CRKII 和 CRKL 通过多个 SH2 和 SH3 结合伙伴重组细胞骨架。 RIN1/CRK(L) 复合体成分的鉴定将为刺激诱导和细胞类型特异性重塑提供新的见解。该提案的第三个目的是评估 RIN1 对神经元可塑性的贡献。 RIN1 可以协调细胞骨架重塑并与其他 RAS 效应子竞争。我们将使用培养的神经元和脑组织来确定神经元刺激如何参与 RAS-RIN1-ABL2-CRK(L) 通路以及该通路的激活如何负向调节可塑性。我们将特别关注树突棘重塑，因为这种现象与学习的联系仍然是推测性的。