Cadherin-catenin Mediated Contact Inhibition of Cell Growth

钙粘蛋白-连环蛋白介导的细胞生长接触抑制

基本信息

批准号：
9193715
负责人：
BARRY M. GUMBINER
金额：
$ 12.68万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9193715
关键词：
Cadherin catenin Mediated Contact Inhibition

项目摘要

DESCRIPTION (provided by applicant): Contact inhibition limits cell growth in tissues, but is highly subject to regulation. It can be overcome in rapidly growing tissues during development, regeneration, and wound healing. Contact inhibition is frequently lost in tumor cells, allowing tumors to grow well beyond their normal tissue constraints. The mechanisms underlying contact inhibition are poorly understood, but cadherin-mediated cell-cell adhesion is thought to play an important role. We have shown that homophilic adhesive binding between E-cadherin proteins at the cell surface, in association with catenins bound to their cytoplasmic domains, directly mediate contact inhibition of growth. We've found that cadherin-catenin mediated contact inhibition occurs via two major pathways; inhibition of growth factor receptor signaling, which we now find results from inhibition of Src family kinases (SFKs); and our preliminary findings also implicate the Hippo signaling pathway, in particular the nuclear localization of the Hippo pathway transcriptional mediator YAP. The Hippo pathway was originally discovered as a regulator of organ size in Drosophila embryos, and recently has been shown to regulate mammalian cell growth, contact inhibition, and tumor development. We have made another novel preliminary finding that growth factor signaling and SFK activity affect YAP nuclear localization and function in some cells, suggesting another important mechanism of Hippo pathway regulation. The overall hypothesis is that E-cadherin-catenin regulates contact inhibition of growth both by stimulating the Hippo signaling pathway and by inhibiting src family kinase (SFK) activity, and in this way it serves to coordinate or balance growth inhibitory signaling with the mitogenic signaling by growth factor receptors. We will first investigate the functional and physiological relationships between E-cadherin-2-catenin mediate adhesion, Hippo pathway signaling, SFK signaling, and Epidermal Growth Factor Receptor (EGFR) signaling. We will determine the molecular mechanisms by which these pathways regulate each other in cell culture models and then test their importance in vivo for tumor formation and normal tissue development in mice. The specific aims are: A. Elucidate the mechanism(s) by which homophilic binding between E-cadherin-catenin complexes regulates signaling through the Hippo pathway. B. Determine how EGFR and SFK signaling regulate the nuclear localization and function of the Hippo pathway transcriptional activator YAP, understand the role of Hippo pathway-mediated growth inhibition in the regulation of mitogenic signaling by EGFR and SFKs, and elucidate the mechanism(s) of regulation SFK activity by E-cadherin-catenin adhesive complexes. C. Evaluate the roles of E-cadherin-catenin-mediated contact inhibition and Hippo pathway signaling in the development of mammary glands and mammary tumors in vivo in mice, and their roles in tumorigenesis driven by Receptor Tyrosine Kinase (RTK) and SFK signaling pathways. Findings from these studies should reveal how contact inhibition regulates normal tissue development and how the loss of contact inhibition leads to the formation and progression of tumors.

描述（由申请人提供）：接触抑制限制组织中的细胞生长，但受到高度调节。在发育，再生和伤口愈合过程中，可以在快速生长的组织中克服它。接触抑制在肿瘤细胞中经常失去，从而使肿瘤的生长超出其正常组织的约束。接触抑制的基础机制知之甚少，但是钙粘蛋白介导的细胞 - 细胞粘附被认为起着重要作用。我们已经表明，与链球菌结合到其细胞质结构域的息肉蛋白相关联，E-钙粘着蛋白之间的同质粘合剂结合直接介导了生长的接触抑制。我们已经发现，钙粘蛋白 - 钙蛋白介导的接触抑制是通过两种主要途径发生的。抑制生长因子受体信号传导，我们现在发现这是由于抑制SRC家族激酶（SFKS）的结果；我们的初步发现也暗示了河马信号通路，特别是河马途径转录介质YAP的核定位。河马途径最初是作为果蝇胚胎中器官大小的调节剂发现的，最近已证明可以调节哺乳动物细胞的生长，接触抑制和肿瘤发育。我们已经提出了另一个新的初步发现，即生长因子信号传导和SFK活性会影响某些细胞中的YAP核定位和功能，这表明河马途径调节的另一种重要机制。总体假设是，通过刺激河马信号传导途径和抑制SRC家族激酶（SFK）活性，E-钙粘蛋白 - - - 蛋白可以调节生长的接触抑制，并通过这种方式来协调或平衡生长抑制性信号与有丝氨酸信号传导通过生长因子受体。我们将首先研究e-钙粘蛋白-2-catenin介导粘附，河马途径信号传导，SFK信号传导和表皮生长因子受体（EGFR）信号之间的功能和生理关系。我们将确定这些途径在细胞培养模型中相互调节的分子机制，然后测试其体内对小鼠肿瘤形成和正常组织发育的重要性。具体目的是：A。阐明电子 - 钙粘蛋白 - 钙蛋白复合物之间均电结合的机制，可以通过河马途径调节信号传导。 B.确定EGFR和SFK信号传导如何调节河马途径转录激活因子YAP的核定位和功能，了解河马途径介导的生长抑制在EGFR和SFKS促成有丝分裂信号传导调节中的作用，并阐明机制E-钙粘蛋白 - 蛋白 - 粘附蛋白粘合剂复合物调节SFK活性。 C.评估E-钙粘蛋白 - 蛋白介导的接触抑制和河马途径信号在小鼠体内乳腺和乳腺肿瘤发育中的发育中的作用。这些研究的发现应揭示接触抑制如何调节正常组织的发展以及接触抑制的丧失如何导致肿瘤的形成和进展。