Proteoglycans of the Plasma Membrane

质膜的蛋白多糖

基本信息

批准号：
7462311
负责人：
ALAN C RAPRAEGER
金额：
$ 24.83万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
1985
资助国家：
美国
起止时间：
1985-09-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7462311
关键词：
Adhesions Affect Basal lamina Behavior Binding Blocking Antibodies Blood Breast Carcinoma Cell Adhesion Cell Line Cell membrane Cell surface Cells Collaborations Complex Core Protein Cytoplasmic Tail Data Dependence Development Environment Epidermal Growth Factor Receptor Epithelial Cells Extracellular Domain Extracellular Matrix Family Family member Growth Factor Hemidesmosomes Heparan Sulfate Proteoglycan Heparin Binding Heparitin Sulfate Human In Vitro Inorganic Sulfates Integrins Invasive Lead Ligands Malignant Epithelial Cell Mammary gland Mediating Modeling Morphogenesis Mus Mutate Neoplasm Metastasis Numbers Organ Peptides Phenotype Process Proteoglycan Proto-Oncogene Protein c-met Recombinants Regulation Research Personnel Role SCID Mice Signal Pathway Signal Transduction Site Small Interfering RNA Techniques Testing Transmembrane Domain Tumor Cell Invasion Unspecified or Sulfate Ion Sulfates Vitronectin Work bone cancer therapy cell motility cell transformation extracellular in vivo inhibitor/antagonist insight laminin-5 matrigel migration mouse model mutant novel programs receptor receptor function research study response syndecan tumor tumorigenesis tumorigenic two-dimensional

项目摘要

DESCRIPTION (provided by applicant): The syndecans are a family of heparan sulfate proteoglycans that function as receptors in extracellular matrix adhesion and growth factor signaling. Of the four family members, syndecan-1 is the most abundant on epithelial cells. The core protein of this receptor has a highly conserved but short cytoplasmic domain, a conserved transmembrane domain, and a more highly variable extracellular )rotein domain (ectodomain). Our recent work has identified several novel interactions of this core protein, showing that each of these discrete domains has unique activity. We plan to examine the unique activities that we have described for the cytoplasmic domain and extracellular domain in human nammary epithelial cells. We will examine the newly discovered role of the syndecan-1 ectodomain in activation of the ava3 integrin. This integrin is expressed on a number of invasive mammary carcinomas and its activated form leads to mammary carinoma cell metastases. We will attempt to define how syndecan-1 regulates the activity of this receptor, and define inhibitors to block its actvity. We will also examine the role of syndecan-1 in the activity of alphavbeta4 integrin. This integrin is critical for the normal polarized phenotype of mammary epithelial cells and their anchorage to their underlying basal lamina ich in laminin 5. However, the integrin is converted to a motility-signaling role on invasive cells. We wil examine how syndecan-1 participates in activity and thus contributes to the tumorigenic phenotype of transformed cells. Finally, we will assess normal and tumorigenic mammary epithelial cells in a three-dimensional matrigel culture, in which the cells display a phenotype more similar to that observed in vivo, and rely on signaling mechanisms differently that in common two-dimensional experiments. We will examine the role of syndecan-1 and the seemingly dramatic role that it has on human mammary epithelial cells in this environment. We will then extend these studies to a tumorigenesis model using the human carcinoma cells in SCID mice. We anticipate that completion of these studies will provide new and unexpected insights into the function of this receptor, and will lead to the development of new cancer treatments.

描述（由申请人提供）：多配体是硫酸乙酰肝素蛋白聚糖家族，在细胞外基质粘附和生长因子信号传导中充当受体。在四个家族成员中，syndecan-1 在上皮细胞上含量最多。该受体的核心蛋白具有高度保守但短的胞质结构域、保守的跨膜结构域和高度可变的胞外蛋白结构域（胞外域）。我们最近的工作已经确定了该核心蛋白的几种新颖的相互作用，表明这些离散结构域中的每一个都具有独特的活性。我们计划检查我们所描述的人类乳腺上皮细胞的细胞质结构域和细胞外结构域的独特活性。我们将研究新发现的 syndecan-1 胞外域在 ava3 整合素激活中的作用。这种整合素在许多浸润性乳腺癌中表达，其激活形式会导致乳腺癌细胞转移。我们将尝试定义 syndecan-1 如何调节该受体的活性，并定义抑制剂来阻断其活性。我们还将研究 syndecan-1 在 alphavbeta4 整合素活性中的作用。这种整合素对于乳腺上皮细胞的正常极化表型及其与层粘连蛋白 5 中的底层基底层的锚定至关重要。然而，整合素在侵袭细胞上转化为运动信号作用。我们将研究 syndecan-1 如何参与活性并从而促进转化细胞的致瘤表型。最后，我们将在三维基质胶培养物中评估正常和致瘤性乳腺上皮细胞，其中细胞表现出与体内观察到的更相似的表型，并且依赖于与常见二维实验不同的信号机制。我们将研究 syndecan-1 的作用以及它在这种环境中对人类乳腺上皮细胞看似戏剧性的作用。然后，我们将使用 SCID 小鼠中的人类癌细胞将这些研究扩展到肿瘤发生模型。我们预计这些研究的完成将为该受体的功能提供新的和意想不到的见解，并将导致新的癌症治疗方法的开发。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor.

Syndecan-1 在血管生成过程中调节 alphavbeta3 和 alphavbeta5 整合素激活，并被新型肽抑制剂 Synstatin 阻断。

DOI：
发表时间：
2009-03-16
期刊：
影响因子：
0
作者：
Beauvais DM;Ell BJ;McWhorter AR;Rapraeger AC
通讯作者：
Rapraeger AC

Syndecan-1 couples the insulin-like growth factor-1 receptor to inside-out integrin activation.

Syndecan-1 将胰岛素样生长因子 1 受体与由内而外的整合素激活结合起来。

DOI：
发表时间：
2010-11-01
期刊：
影响因子：
4
作者：
Beauvais, DeannaLee M;Rapraeger, Alan C
通讯作者：
Rapraeger, Alan C

Interaction of syndecan and alpha6beta4 integrin cytoplasmic domains: regulation of ErbB2-mediated integrin activation.

Syndecan 和 α6β4 整合素胞质结构域的相互作用：ErbB2 介导的整合素激活的调节。

DOI：
10.1074/jbc.m110.102137
发表时间：
2010-04-30
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Haiyao Wang;L. Leavitt;Ravishankar Ramaswamy;A. Rapraeger
通讯作者：
A. Rapraeger

Vascular endothelial-cadherin stimulates syndecan-1-coupled insulin-like growth factor-1 receptor and cross-talk between ýýVýý3 integrin and vascular endothelial growth factor receptor 2 at the onset of endothelial cell dissemination during angiogenesis.

血管内皮钙粘蛋白在血管生成过程中内皮细胞播散开始时刺激 Syndecan-1 偶联的胰岛素样生长因子 1 受体以及 αVα3 整合素和血管内皮生长因子受体 2 之间的串扰。

DOI：
发表时间：
2013-05
期刊：
影响因子：
0
作者：
Rapraeger, Alan C;Ell, Brian J;Roy, Madhuchhanda;Li, Xuehui;Morrison, Orrianne R;Thomas, Grant M;Beauvais, DeannaLee M
通讯作者：
Beauvais, DeannaLee M

Reproductive Biology and Endocrinology Open Access Syndecans in Tumor Cell Adhesion and Signaling

生殖生物学和内分泌学开放存取多聚糖在肿瘤细胞粘附和信号传导中的作用

DOI：
10.1186/2191-219x-1-20
发表时间：
2011-09-01
期刊：
EJNMMI Research
影响因子：
3.2
作者：
Rousseau C;Ruellan AL;Bernardeau K;Kraeber-Bodéré F;Gouard S;Loussouarn D;Saï-Maurel C;Faivre-Chauvet A;Wijdenes J;Barbet J;Gaschet J;Chérel M;Davodeau F
通讯作者：
Davodeau F