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

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

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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.

信号序列靶向新翻译的蛋白质到细胞内外的特定位置，以及彼此之间，在细胞生物学中起关键作用。除了他们的经典目标功能，许多非 - 近年来已经报道了特定信号辣椒的规范功能，主要是在较低的生物体中，而且还在桉树细胞中。但是，关于信号序列的生物学，还有很多尚待学习这已成为药物开发的新重点。血管内皮生长因子（VEGF）是血管生成中的原型生长因子，发育，生长，成人稳态和对损伤的反应，在广泛的疾病中失调，包括缺血有关心血管疾病，糖尿病性视网膜病和恶性肿瘤。 VEGF效应主要由其介导高亲和力与VEGF受体（VEGFR）-2触发几个下游信号的激活途径。这是一个严格控制的过程，具有多层调节，以确保精心调整的信号。内皮和平滑肌细胞衍生的神经蛋白样蛋白（DCBLD2）是一种积分膜蛋白具有异常长的两辅助剂组织信号序列。我们已经将DCBLD2确定为 DCBLD2与VEGFR合作 2并通过调节VEGFR-2-VE-钙粘蛋白 - 蛋白质酪氨酸磷酸酶复合酶复合物调节VEGF信号传导形成。在寻找与VEGFR-2相互作用的DCBLD2域，我们意外地确定了 DCBLD2信号序列与VEGFR-2之间的功能相互作用。 DCBLD2信号序列表达或添加合成肽包含其疏水性的C末端部分的表达或添加细胞促进了VEGF信号转移。这导致我们假设DCBLD2信号序列调节 VEGF（可能是其他生长因子）信号转导并调节血管生成，还提高了其他类似结构化的信号序列可能在生长因子信号传导中起调节作用的可能性。在这里，我们试图扩大这些观察结果的范围以定义，并确定行动机理， DCBLD2信号序列在VEGF和相关信号通路上的靶向后函数。为此，我们的具体目的是研究VEGF信号中DCBLD2信号序列的非典型功能转导和评估外源性DCBLD2信号序列相关宠物对VEGF的影响信号传导和血管生成。提出的实验为信号建立了新的靶向后函数生长因子信号转移的序列，并为未来的信号序列发展奠定了基础基于血管生成，而且可能是其他疾病，基于基于治疗。