Regulation of insulin-like growth factor I receptor tyrosine kinase

胰岛素样生长因子I受体酪氨酸激酶的调节

基本信息

批准号：
7752492
负责人：
W Todd MILLER
金额：
$ 28.95万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7752492
关键词：
Active Sites Antineoplastic Agents Arginine Biochemical C-terminal Catalytic Domain Cells Cellular biology Chemicals Collaborations Complex Computer Simulation Crystallization Cytokine Inducible SH2-Containing Protein Cytoplasmic Tail Data Development Diabetes Mellitus Dimerization Drug Design Fibroblasts Fluorescence Glutamine Goals Human IGF1R gene In Vitro Insulin Receptor Insulin-Like-Growth Factor I Receptor Kinetics Length Ligand Binding Malignant - descriptor Malignant Neoplasms Measures Molecular Molecular Conformation Mus Mutate Mutation Non-Insulin-Dependent Diabetes Mellitus PTPN1 gene Patients Peptide Hydrolases Peptides Phosphorylation Phosphorylation Site Phosphotransferases Play Process Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Proto-Oncogene Protein c-kit Receptor Protein-Tyrosine Kinases Regulation Role Signal Transduction Site Structure Testing Tissues Tyrosine analog base cell type dimer enzyme activity extracellular gel electrophoresis inhibitor/antagonist medical schools mutant overexpression receptor research study tandem mass spectrometry

项目摘要

DESCRIPTION (provided by applicant): This project focuses on the molecular mechanisms that regulate the insulin-like growth factor I receptor (IGF1R). Constitutive or inappropriate activation of many tyrosine kinases plays a role in the progression and development of various forms of human cancer. Recent evidence has implicated IGF1R in malignant transformation, and IGF1R has emerged as a target for anticancer drug design. No clinically effective inhibitors for IGF1R have been developed to date. Aim 1 studies the mechanism of IGF1R autophosphorylation. Upon ligand binding, IGF1R is activated by phosphorylation at three sites in the activation loop of the kinase catalytic domain. We will determine the functional significance of each phosphorylation using biochemical, biophysical, and computational approaches. Aim 2: In collaboration with Dr. Stevan Hubbard, we recently determined a dimeric structure of IGF1R which potentially represents an intermediate in the autophosphorylation process. We will carry out biochemical and cell biology experiments to test this possibility. The dimeric structure may also explain the effect of an Arg-to-Gln mutation in insulin receptor observed in two patients with non-insulin- dependent diabetes. Aim 3 will explore the hypothesis that the juxtamembrane region of IGF1R is involved in autoinhibition. We will study juxtamembrane mutants in fibroblasts derived from IGF1R-deficient mice. We will also analyze the purified proteins using biochemical and structural approaches.

描述（由申请人提供）：该项目重点研究调节胰岛素样生长因子 I 受体 (IGF1R) 的分子机制。许多酪氨酸激酶的组成性或不适当激活在各种形式的人类癌症的进展和发展中发挥着作用。最近的证据表明 IGF1R 与恶性转化有关，并且 IGF1R 已成为抗癌药物设计的目标。迄今为止，尚未开发出临床有效的 IGF1R 抑制剂。目标 1 研究 IGF1R 自磷酸化的机制。配体结合后，IGF1R 通过激酶催化结构域激活环中三个位点的磷酸化而被激活。我们将使用生物化学、生物物理和计算方法确定每个磷酸化的功能意义。目标 2：我们最近与 Stevan Hubbard 博士合作，确定了 IGF1R 的二聚结构，它可能代表自磷酸化过程中的中间体。我们将进行生化和细胞生物学实验来测试这种可能性。二聚体结构也可以解释在两名非胰岛素依赖性糖尿病患者中观察到的胰岛素受体中精氨酸到谷氨酰胺突变的影响。目标 3 将探讨 IGF1R 近膜区域参与自抑制的假设。我们将研究来自 IGF1R 缺陷小鼠的成纤维细胞的近膜突变体。我们还将使用生化和结构方法分析纯化的蛋白质。