Regulation of tyrosine kinase signaling through interaction with membrane lipids

通过与膜脂相互作用调节酪氨酸激酶信号传导

基本信息

批准号：
8887665
负责人：
VADIM V GAPONENKO
金额：
$ 43万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8887665
关键词：
1-Phosphatidylinositol 3-Kinase Address Affinity Amino Acids Binding Binding Proteins Biochemical Catalytic Domain Cell Line Cell Nucleus Cell Proliferation Cell membrane Cell physiology Cells Cellular biology Characteristics Complex Cytoplasm Data Epithelial Epithelial Cells Epithelium Exhibits Family Gastrointestinal tract structure Gene Deletion Genes Growth Growth Factor Receptors Head Human In Vitro Intestines Lead Lipid Binding Lipids Malignant Neoplasms Malignant neoplasm of prostate Membrane Membrane Lipids Membrane Proteins Mesenchymal Modeling Modification Molecular Genetics Mus Mutation Neoplasm Metastasis Nuclear Nuclear Protein Oncogenic Outcome PTEN gene PTK6 gene Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipids Phosphoric Monoester Hydrolases Phosphotransferases Phosphotyrosine Play Production Prostate Prostatic Diseases Prostatic Neoplasms Protein Tyrosine Kinase Recruitment Activity Regulation Research Role SH3 Domains Signal Pathway Signal Transduction Skin Staging Surface Plasmon Resonance Testing Therapeutic Tumor Suppressor Proteins Xenograft Model cancer cell cell transformation cell type design flexibility human protein tyrosine kinase brk in vivo inhibitor/antagonist inorganic phosphate malignant breast neoplasm migration mouse model myristoylation nanodisk neoplastic cell novel novel strategies novel therapeutics palmitoylation prevent prostate cancer cell prostate cancer cell line prostate carcinogenesis public health relevance src Homology Region 2 Domain therapy development tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that contains SH3 and SH2 domains, but lacks an SH4 domain that promotes membrane localization. Lack of membrane targeting facilitates flexibility in its intracellular localization and access to substrates. In differentiated prostate epithelial cells, PTK6 is primariy found in the nucleus. However, active PTK6 associates with the plasma membrane in prostate cancer, and its increased expression is correlated with metastasis and poor survival. We found that membrane-associated PTK6 promotes cell transformation, the epithelial mesenchymal transition, and tumor cell metastasis, while nuclear PTK6 inhibits growth. We designed a collaborative proposal to address the question, "How is PTK6 recruited to the plasma membrane where it promotes tumorigenesis?" Our preliminary data suggest PTK6 directly binds phosphate-rich lipids, including phosphatidylinositol-(3, 4, 5)-trisphosphate (PIP3), at the plasma membrane. Increased production of PIP3 is commonly observed in cancer due to activation of PI3K and/or mutation of the tumor suppressor lipid phosphatase PTEN. We hypothesize that phosphate-rich lipids, such as PIP3 regulate the recruitment and activation of PTK6 at the plasma membrane to drive tumorigenesis and metastases. Highly synergistic studies proposed by Dr. Tyner, a cell biologist, and Dr. Gaponenko, a structural biochemist, use an array of biochemical, biophysical, molecular, genetic and cell biology approaches to: (i) Investigate PTK6 lipid binding; (ii) Identify domains in PTK6 required for lipid binding; (iii) Determine contributions of PI3K/PTEN/PIP3 to activation of PTK6 at the membrane in prostate cancer cells; and (iv) Examine contributions of PTK6 membrane binding to prostate tumorigenesis in mice with prostate specific deletion of the gene encoding the tumor suppressor PTEN. The results of this research will define a novel mechanism for intracellular tyrosine kinase membrane targeting and activation, and could identify novel strategies to inhibit PTK6 in cancer. In additio, alterations in PTK6 intracellular localization or expression may provide a unique marker for staging prostate cancers.

描述（由申请人提供）：蛋白酪氨酸激酶 6 (PTK6) 是一种细胞内酪氨酸激酶，包含 SH3 和 SH2 结构域，但缺乏促进膜定位的 SH4 结构域。缺乏膜靶向有利于其细胞内定位和接触底物的灵活性。在分化的前列腺上皮细胞中，PTK6 主要存在于细胞核中，但在前列腺癌中，活性 PTK6 与质膜相关。我们发现膜相关的 PTK6 促进细胞转化、上皮间质转化和肿瘤细胞转移，而核 PTK6 抑制生长，我们设计了一个合作提案来解决这个问题。 PTK6 如何被招募到质膜并促进肿瘤发生？”我们的初步数据表明 PTK6 直接结合富含磷酸盐的脂质，包括血浆中的磷脂酰肌醇-(3,4,5)-三磷酸 (PIP3) 由于 PI3K 的激活和/或肿瘤抑制脂质磷酸酶 PTEN 的突变，在癌症中经常观察到 PIP3 的产生增加。细胞生物学家 Tyner 博士和结构生物化学家 Gaponenko 博士提出的高度协同研究使用了一系列药物来驱动肿瘤发生和转移。生物化学、生物物理、分子、遗传和细胞生物学方法：(i) 研究 PTK6 脂质结合；(ii) 识别 PTK6 中脂质结合所需的结构域；(iii) 确定 PI3K/PTEN/PIP3 对 PTK6 激活的贡献。 (iv) 在编码肿瘤抑制因子 PTEN 的前列腺特异性缺失的小鼠中，检查 PTK6 膜结合对前列腺肿瘤发生的贡献。将定义细胞内酪氨酸激酶膜靶向和激活的新机制，并可能确定抑制癌症中 PTK6 的新策略。此外，PTK6 细胞内定位或表达的改变可能为前列腺癌分期提供独特的标记。