p120-catenin sub-family functions

p120-连环蛋白亚家族功能

• 批准号: 7920572
• 负责人: PIERRE D MCCREA
• 金额: $ 5.74万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920572
• 关键词: Address; Adult; Amphibia; Animals; Area; Attention; Binding; Biochemical; Biology; Cadherins; Cell Adhesion; Cell Adhesion Molecules; Cell Line; Cell Nucleus; Cell membrane; Cell-Cell Adhesion; Cells; Colon Carcinoma; Complement; Cytoplasm; Cytoplasmic Tail; Development; Developmental Process; Embryo; Embryonic Development; Evaluation; Family; Family member; Funding; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Guanosine Triphosphate Phosphohydrolases; Health; Human; Injection of therapeutic agent; Knowledge; Laboratories; Learning; Left; Link; Mammalian Cell; Maps; Mediating; Membrane; Metabolic; Molecular; Monomeric GTP-Binding Proteins; Oligonucleotides; Pathway interactions; Phenotype; Phosphorylation Site; Phosphotransferases; Play; Protein Family; Proteins; Rana; Reagent; Regulation; Role; Signal Pathway; Signal Transduction; System; TCF Transcription Factor; Testing; Tissues; Work; Xenopus laevis; beta catenin; cell motility; delta-catenin; human disease; interest; knock-down; melanoma; member; multicatalytic endopeptidase complex; novel; protein complex; response; rho

DESCRIPTION (provided by applicant): The catenin proteins contribute to the biology of all animal cells and tissues, displaying essential embryonic and adult functions within differing sub-cellular compartments. For example, in addition to binding the inner (cytoplasmic) domain of cadherin trans-membrane cell-cell adhesion molecules, beta-catenin is well known to play an essential role in Wnt developmental signaling where within the nucleus it regulates transcription from specific gene targets. These gene targets are not only important for normal embryogenesis but also for the progression of human diseases including colon carcinoma and melanoma. In this renewal application, we focus upon the roles of less understood members of the catenin family of proteins, specifically members of the p120-catenin sub-family (p120- catenin; ARVCF-catenin; delta-catenin). A major interest is how upstream Wnt- pathway signals produce a network of p120 sub-family responses in addition to those better known for beta-catenin. Our aims include elucidating the biochemical mechanisms by which Wnt signals act upon p120 sub-family members. Evidence gathered for p120-catenin itself suggests that such regulation involves kinase activity and modulation of p120-catenin protein stability. Preliminary evidence relating to ARVCF and delta-catenin likewise leaves open the possibility of Wnt-pathway responsiveness, with for example, identification of two novel delta-catenin protein complexes involving known Wnt- pathway components. Overall, our work is aimed at expanding the scope of our understanding of catenin biology, with particular regard to the novel roles of p120-subF proteins in Wnt signaling. For our studies, we will predominantly employ Xenopus laevis (frog) embryos. This vertebrate system offers facile introduction (micro-injection) of exogenous constructs/ reagents, rapid external development and many biochemical and molecular advantages. For functional analysis, we will utilize knock-down (morpholino oligonucleotide), exogenous expression and rescue approaches in conjunction with the study of developmental phenotypes and biochemical and molecular tests of protein complex formation or target gene activity. To complement our work in developing amphibian embryos, we will employ select mammalian cell lines, for example, Wnt-responsive HEK293T cells. Project narrative: The Wnt signaling pathway is required for the development of all animals, while it's proper later regulation remains important in maintaining health. For example, the progression of >90% of human colon carcinomas and melanomas involves pathological activation of the Wnt pathway. Our proposal examines the functions of a group of proteins belonging to the p120-catenin sub-family, that we have evidence and hypothesize participates in Wnt signaling, and whose study will assist in understanding of both normal development and human disease.

描述（由申请人提供）：Catenin蛋白有助于所有动物细胞和组织的生物学，在不同的亚细胞隔室内显示必需的胚胎和成人功能。例如，除了结合钙粘蛋白反膜细胞 - 细胞粘附分子的内部（细胞质）结构域外，β-catenin众所周知，β-蛋白酶在Wnt发育信号传导中起着至关重要的作用，其中它在原子核中它在核中调节从特定基因靶标进行转录。这些基因靶标不仅对正常的胚胎发生很重要，而且对于包括结肠癌和黑色素瘤在内的人类疾病的发展也很重要。在这种续签应用中，我们关注蛋白质蛋白质家族的知识成员的作用，特别是P120-Catenin sub-family（p120- catenin; arvcf-catenin; delta-catenin）的成员。一个主要的兴趣是，除了以β-catenin而闻名的人之外，上游WNT途径信号如何产生P120亚家族响应网络。我们的目标包括阐明Wnt信号对P120亚家族成员作用的生化机制。针对P120-Catenin本身收集的证据表明，这种调节涉及激酶活性和P120-Catenin蛋白稳定性的调节。与ARVCF和Delta-catenin有关的初步证据同样开放了Wnt-pathway响应性的可能性，例如，鉴定了两个新型的Delta-catenin蛋白蛋白复合物，涉及已知的Wnt-Pathway成分。总体而言，我们的工作旨在扩大我们对Catenin生物学的理解范围，特别是关于P120-SUBF蛋白在WNT信号传导中的新作用。在我们的研究中，我们将主要采用爪蟾（青蛙）胚胎。该脊椎动物系统提供了外源构建体/试剂，快速外部发育以及许多生化和分子优势的简便引入（微注射）。为了进行功能分析，我们将利用敲除（吗啡寡核苷酸），外源表达和救援方法以及对蛋白质复合物形成或靶基因活性的发育表型以及生化和分子测试的研究结合。为了补充我们开发两栖胚胎的工作，我们将采用某些哺乳动物细胞系，例如Wnt响应性HEK293T细胞。项目叙述：所有动物的开发都需要WNT信号通路，而适当的后期法规对于维持健康仍然很重要。例如，> 90％的人类结肠癌和黑色素瘤的进展涉及WNT途径的病理激活。我们的建议研究了属于P120-catenin sub-family的一组蛋白质的功能，我们有证据并假设参与Wnt信号，其研究将有助于理解正常发育和人类疾病。