Signal peptides and growth factor signaling

信号肽和生长因子信号传导

基本信息

批准号：
10417764
负责人：
MEHRAN M SADEGHI
金额：
$ 66.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10417764
关键词：
Address Adult Affinity Amino Acids Area Base Sequence Binding Biology Blood Vessels C-terminal Cardiovascular Diseases Cells Cellular biology Charge Complex Cultured Cells Development Diabetic Retinopathy Disease Endothelial Cells Endothelium Ensure Future Growth Growth Factor Growth Factor Receptors Homeostasis Hydrophobicity Integral Membrane Protein Ischemia KDR gene Knowledge Lead Length Location Lower Organism Malignant Neoplasms Mediating Molecular Myocardial Ischemia N-terminal Names Neuropilins Pathologic Peptide Signal Sequences Peptides Play Process Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Regulation Reporting Role Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Specificity Structure Therapeutic Time Translating Vascular Endothelial Growth Factors angiogenesis cell growth drug development experimental study in vivo interest mouse model novel novel therapeutics receptor response response to injury signal peptidase synthetic peptide uptake vascular endothelial cadherin-2 wound healing

项目摘要

Signal sequences target newly translated proteins to specific locations within and outside the cell, and accordingly, play a key role in cell biology. Beyond their classical targeting functions, a number of non- canonical functions of specific signal peptides have been reported in recent years, mostly in lower organisms, but also in eucaryotic cells. However, much remains to be learned regarding the biology of signal sequences, which have emerged as a new focus for drug development. Vascular endothelial growth factor (VEGF) is the prototypic growth factor in angiogenesis, a key process during development, growth, adult homeostasis, and response to injury, which is dysregulated in a broad spectrum of diseases, including ischemia-related cardiovascular diseases, diabetic retinopathy and malignancy. The VEGF effects are primarily mediated by its high affinity binding to VEGF receptor (VEGFR)-2 which triggers activation of several downstream signaling pathways. This is a tightly controlled process with multiple layers of regulation to ensure a finely tuned signal. Endothelial and smooth muscle cell-derived neuropilin-like protein (DCBLD2) is an integral membrane protein with an unusually long, two-subdomain organization signal sequence. We have identified DCBLD2 as a regulator of VEGF signaling and developmental and ischemic angiogenesis. DCBLD2 associates with VEGFR- 2 and regulates VEGF signaling by modulating VEGFR-2-VE-cadherin-protein tyrosine phosphatase complex formation. In search of DCBLD2 domain(s) involved in its interaction with VEGFR-2, unexpectedly we identified a functional interaction between the DCBLD2 signal sequence and VEGFR-2. DCBLD2 signal sequence expression, or addition of a synthetic peptide encompassing its hydrophobic, C-terminal moiety to cultured cells promoted VEGF signal transduction. This led us to hypothesize that DCBLD2 signal sequence regulates VEGF (and possibly other growth factors’) signal transduction and modulates angiogenesis, also raising the possibility that other similarly structured signal sequences may play a regulatory role in growth factor signaling. Here, we seek to expand the scope of these observations to define, and determine the mechanism of action of, the post-targeting functions of DCBLD2 signal sequence on VEGF and related signaling pathways. To this end, our specific aims are to investigate non-canonical functions of DCBLD2 signal sequence in VEGF signal transduction and evaluate the effects of exogenous DCBLD2 signal sequence-related peptides on VEGF signaling and angiogenesis. The proposed experiments establish a novel post-targeting function for signal sequences in growth factor signal transduction and set the stage for future development of signal sequence- based therapeutics, not only for angiogenesis, but potentially other disorders.

信号序列将新翻译的蛋白质靶向细胞内外的特定位置，并且因此，除了其经典的靶向功能之外，许多非-细胞生物学也发挥着关键作用。近年来报道了特定信号肽的典型功能，主要是在低等生物中，但在真核细胞中也如此。然而，关于信号序列的生物学还有很多东西需要了解。血管内皮生长因子（VEGF）已成为药物开发的新焦点。血管生成中的原型生长因子，血管生成是发育、生长、成人体内平衡和发育过程中的关键过程对损伤的反应，这种反应在多种疾病中失调，包括与缺血相关的疾病心血管疾病、糖尿病视网膜病变和恶性肿瘤 VEGF 的作用主要是由其介导的。与 VEGF 受体 (VEGFR)-2 高亲和力结合，触发多个下游信号传导的激活这是一个严格控制的过程，具有多层调节，以确保微调信号。内皮细胞和平滑肌细胞来源的神经毡蛋白样蛋白 (DCBLD2) 是一种整合膜蛋白具有异常长的两个子域组织信号序列，我们已将 DCBLD2 鉴定为一个 DCBLD2 是 VEGF 信号传导以及发育和缺血性血管生成的调节因子，与 VEGFR- 相关。 2 并通过调节 VEGFR-2-VE-钙粘蛋白-蛋白酪氨酸磷酸酶复合物来调节 VEGF 信号转导在寻找参与其与 VEGFR-2 相互作用的 DCBLD2 结构域时，我们意外地发现了这一点。 DCBLD2信号序列和VEGFR-2之间的功能性相互作用。表达或添加包含其疏水性 C 末端部分的合成肽到培养物中细胞 VEGF 信号转导的促进这导致我们与 DCBLD2 信号序列的调节进行斗争。 VEGF（可能还有其他生长因子）信号转导并调节血管生成，同时提高其他类似结构的信号序列可能在生长因子信号传导中发挥调节作用。在这里，我们寻求扩大这些观察的范围，以定义和确定作用机制， DCBLD2信号序列对VEGF及相关信号通路的后靶向作用。我们的具体目标是研究 DCBLD2 信号序列在 VEGF 信号中的非规范功能转导并评估外源DCBLD2信号序列相关肽对VEGF的影响所提出的实验建立了一种新的信号后靶向功能。生长因子信号转导中的序列，并为信号序列的未来发展奠定基础- 基于疗法，不仅针对血管生成，还针对其他潜在疾病。