Regulation of Her2/neu by activation loop phosphorylation and ALG-2

通过激活环磷酸化和 ALG-2 调节 Her2/neu

基本信息

批准号：
7497501
负责人：
RON BOSE
金额：
$ 14.34万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-18 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7497501
关键词：
1-Phosphatidylinositol 3-Kinase Affect Antibodies Apoptosis Appendix Applications Grants Baculoviruses Binding Binding Sites Biochemical Biological Assay Biotinylation Calcium-Binding Proteins Cell surface Cells Class Collaborations Coupled Cultured Cells Dimerization Doctor of Medicine Doctor of Philosophy Epidermal Growth Factor Receptor ErbB Receptor Family Protein Event Extracellular Domain Fellowship Genes Goals Grant Human Immunofluorescence Immunologic In Vitro Insulin Receptor Internal Medicine Knowledge Laboratories Length Link Lipids Literature Malignant Neoplasms Mammary Neoplasms Mammary gland Measures Mediating Medical Medical Oncology Memorial Sloan-Kettering Cancer Center Mitogen-Activated Protein Kinases Modeling Molecular Monoclonal Antibodies Mus Mutate Mutation Pathway interactions Patients Pattern Phospholipase Phosphorylation Phosphorylation Site Phosphotransferases Process Protein Databases Protein Kinase Protein Overexpression Protein Tyrosine Kinase Proteins Proteomics Publishing Rate Receptor Protein-Tyrosine Kinases Receptor Signaling Recombinants Regulation Research Research Personnel Residencies Resistance Roche brand of trastuzumab STAT1 gene Scientist Second Messenger Systems Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Site Small Interfering RNA Testing Training Programs Transgenic Mice Translational Research Trastuzumab Tyrosine Tyrosine Phosphorylation Ubiquitination Universities Vesicle Western Blotting Work base cancer therapy cell transformation design dimer inhibitor/antagonist kinase inhibitor knock-down malignant breast neoplasm monomer novel oncology outcome forecast programs protein protein interaction receptor receptor internalization research study second messenger small molecule src-Family Kinases ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): The candidate, Ron Bose, M.D., Ph.D., is a graduate of the Medical Scientist Training Program held jointly at Cornell University- Rockefeller University- Memorial Sloan-Kettering Cancer Center. His Ph.D. research, conducted at Memorial Sloan Kettering, studied a lipid second messenger pathway which induced apoptosis. Dr. Bose completed residency in Internal Medicine in 2002 and entered Medical Oncology fellowship at Johns Hopkins University. His goals are to pursue basic and translational research by applying proteomics to study signal transduction pathways in breast cancer. He has published a proteomic study of Her2/neu tyrosine kinase signaling (Appendix A) and systematically compared these results to proteomic studies of Epidermal growth factor receptor (EGFR) signaling already in the literature. In this proposal, he plans to pursue two related proteomic findings, Her2/neu activation loop phosphorylation on tyrosine 877 and Her2/neu induced phosphorylation of Apoptosis-linked gene 2 (ALG2), with focused mechanistic experiments. Both activation loop phosphorylation and ALG-2 phosphorylation may be regulatory mechanisms for Her2/neu function and may help control the receptor tyrosine kinase after dimerization has occurred. The activation loop is a major structural feature of kinase domains and has been shown to regulate the activity of insulin receptor kinase and Src. ALG-2 interacts with proteins involved in receptor internalization. Internalization and degradation of Her2/neu is a major mechanism of action of the anti-Her2/neu antibody, trastuzumab (Herceptin). In this proposal, the specific aims will test: 1) if recombinant Her2/neu kinase domain can in vitro autophosphorylate itself on the activation loop and the interaction of this process with a recent model of kinase domain dimerization, 2) if mutation of the activation loop site (Y877F) affects downstream signaling and trastuzumab-induced Her2/neu internalization, 3) if ALG-2 and its interacting protein Alix/AIP1 affect trastuzumab induced Her2/neu internalization and degradation. This research will be performed in the Department of Oncology, Johns Hopkins University. Relevance: Her2/neu and EGFR are protein kinases involved in multiple human cancers. Careful, mechanistic study of their regulation will result in better application of current targeted therapies and possible design of a new class of kinase inhibitors for the treatment of cancer.

描述（由申请人提供）：候选人，医学博士Ron Bose，博士学位，是在康奈尔大学 - 洛克菲勒大学联合举办的医学科学家培训计划的毕业生 - 纪念Sloan-Kettering癌症中心。他的博士学位在纪念斯隆·凯特林（Memorial Sloan Kettering）进行的研究研究了脂质第二信使途径，诱导凋亡。 Bose博士于2002年完成了内科住院医师，并在约翰·霍普金斯大学（Johns Hopkins University）进入了医学肿瘤学奖学金。他的目标是通过应用蛋白质组学来研究乳腺癌中的信号转导途径来进行基础和转化研究。他已经发表了一项对HER2/NEU酪氨酸激酶信号传导（附录A）的蛋白质组学研究，并系统地将这些结果与文献中已经已经已经存在的表皮生长因子受体（EGFR）信号进行了比较。在该提案中，他计划追求两个相关的蛋白质组学发现，即酪氨酸877上的HER2/NEU激活环磷酸化和HER2/NEU诱导的凋亡连锁基因2（ALG2）的磷酸化，并进行了重点机械实验。激活环磷酸化和ALG-2磷酸化均可能是HER2/NEU功能的调节机制，并且可能有助于在发生二聚化后控制受体酪氨酸激酶。激活环是激酶结构域的主要结构特征，已被证明可以调节胰岛素受体激酶和SRC的活性。 ALG-2与涉及受体内在化的蛋白质相互作用。 HER2/NEU的内在化和降解是抗HER2/NEU抗体Trastuzumab（Herceptin）的主要作用机理。 In this proposal, the specific aims will test: 1) if recombinant Her2/neu kinase domain can in vitro autophosphorylate itself on the activation loop and the interaction of this process with a recent model of kinase domain dimerization, 2) if mutation of the activation loop site (Y877F) affects downstream signaling and trastuzumab-induced Her2/neu internalization, 3) if ALG-2 and它的相互作用蛋白ALIX/AIP1影响曲妥珠单抗诱导HER2/NEU内在化和降解。这项研究将在约翰·霍普金斯大学肿瘤学系进行。相关性：HER2/NEU和EGFR是与多种人类癌症有关的蛋白激酶。仔细的，对其调节的机理研究将使当前的靶向疗法更好地应用，并可能设计一种新的激酶抑制剂来治疗癌症。