Signal peptides and growth factor signaling

信号肽和生长因子信号传导

• 批准号: 10586055
• 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
• 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/10586055
• 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; Homeostasis; Hydrophobicity; Integral Membrane Protein; Ischemia; KDR gene; Knowledge; Learning; Length; Location; Lower Organism; Malignant Neoplasms; Mediating; Molecular; Myocardial Ischemia; N-terminal; Names; Neuropilins; Pathologic; Peptide Signal Sequences; Peptides; Play; Process; Protein Tyrosine Phosphatase; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Site; Smooth Muscle Myocytes; Specificity; Structure; Therapeutic; Time; Translating; Vascular Endothelial Growth Factors; angiogenesis; cadherin 5; drug development; experimental study; in vivo; interest; mouse model; novel; novel therapeutics; prototype; receptor; response; response to injury; signal peptidase; synthetic peptide; uptake; wound healing

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， 因此，在细胞生物学中起着关键作用。除了其传统的目标功能，一些非- 近年来已经报道了特异性信号肽的典型功能，主要是在低等生物中， 也存在于真核细胞中。然而，关于信号序列的生物学还有很多东西要学， 这已经成为药物开发的新焦点。血管内皮生长因子（VEGF）是一种 血管生成中的原型生长因子，是发育、生长、成人体内平衡和 对损伤的反应，其在广泛的疾病中失调，包括缺血相关的 心血管疾病、糖尿病视网膜病变和恶性肿瘤。VEGF的作用主要是通过其 与VEGF受体（VEGFR）-2的高亲和力结合，其触发几种下游信号传导的激活 途径。这是一个严格控制的过程，具有多层调节，以确保微调信号。 内皮和平滑肌细胞源性神经纤毛蛋白样蛋白（DCBLD 2）是一种完整的膜蛋白 具有异常长的两子域组织信号序列。我们已经确定DCBLD 2是一种 VEGF信号传导和发育和缺血性血管生成的调节剂。DCBLD 2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信号传导 阵在寻找参与其与VEGFR-2相互作用的DCBLD 2结构域时，我们意外地发现了 DCBLD 2信号序列和VEGFR-2之间的功能性相互作用。DCBLD 2信号序列 表达，或将包含其疏水性C-末端部分的合成肽添加到培养的 细胞促进VEGF信号转导。这使我们假设DCBLD 2信号序列调节 VEGF（以及可能的其他生长因子）信号转导和调节血管生成，也提高了 其他类似结构的信号序列可能在生长因子信号传导中起调节作用。 在这里，我们试图扩大这些观察的范围，以定义和确定的作用机制， DCBLD 2信号序列对VEGF及相关信号通路的后靶向作用。为此目的， 我们的具体目标是研究DCBLD 2信号序列在VEGF信号中的非典型功能 转导，并评估外源性DCBLD 2信号序列相关肽对VEGF的影响 信号传导和血管生成。该实验建立了一种新的信号后靶向函数 序列在生长因子信号转导中的作用，并为信号序列的未来发展奠定了基础- 基于治疗，不仅是血管生成，但潜在的其他疾病。