Tumor gene expression in vitro and in vivo

我们过去对生长的大部分研究都关注ras癌基因及其阳性调节因子，ras特异性鸟嘌呤核苷酸交换因子（ras - gnef），它在信号转导中起关键作用。我们最近将注意力转向e -钙粘蛋白及其在调节生长和信号传导中的作用。e -钙粘蛋白是一种必需的黏附蛋白，也是肿瘤中经常沉默的肿瘤抑制因子。e -钙粘蛋白最初被描述为一种结构蛋白，最近被认为可以调节信号传导。迄今为止，与E-cadherin调控的主要生物学相关信号分子是β -catenin，它与E-cadherin非共价结合，是Wnt信号通路的关键组成部分。然而，虽然粘附是E-cadherin的标志性功能，但其对β -catenin的调节并不依赖于E-cadherin的粘附功能。我们现在已经发现e -钙粘蛋白可以以粘附依赖的方式负调节不同类型的受体酪氨酸激酶的配体依赖激活，包括EGFR/Neu， IGF1R和c-Met。相比之下，E-cadherin不调节组成活性突变受体酪氨酸激酶（Neu*）或LPA受体或毒蕈碱受体的配体依赖性激活，这是两种G蛋白偶联受体。E-cadherin依赖性粘附限制了EGFR-CFP在质膜中的迁移，消除了高亲和力的EGF和IGF-1结合位点，从而损害了配体激活其同源受体的能力。结果表明，受体酪氨酸激酶通过其可溶性配体的负调节是生理性的、特异性的和粘附依赖性的。由于受体酪氨酸激酶参与多种细胞过程，包括营养、生长和分化，数据表明e -钙粘蛋白可以调节这些过程。受体酪氨酸激酶调节的取消也可能有助于e -钙粘蛋白在肿瘤中的频繁沉默。

Much of our past research on growth has been concerned with the ras oncogene and its positive regulators, the Ras-specific guanine nucleotide exchange factors (Ras-GNEFs), which play a key role in signal transduction. We have recently turned our attention to E-cadherin and its role in the regulation of growth and signaling. E-cadherin is an essential adhesion protein that is also a tumor suppressor frequently silenced in tumors. Originally described as a structural protein, E-cadherin has more recently been recognized to regulate signaling. The principal biologically relevant signaling molecule thus far implicated as being regulated by E-cadherin is Beta-catenin, which binds non-covalently to E-cadherin and is a key component of the Wnt signaling pathway. However, although adhesion is the hallmark function of E-cadherin, its regulation of Beta-catenin does not depend on the adhesive function of E-cadherin. We have now found that E-cadherin can negatively regulate, in an adhesion-dependent manner, the ligand-dependent activation of divergent classes of receptor tyrosine kinases, including EGFR/Neu, IGF1R, and c-Met. By contrast, E-cadherin did not regulate a constitutively active mutant receptor tyrosine kinase (Neu*) or the ligand-dependent activation of LPA receptors or muscarinic receptors, which are two G protein coupled receptors. E-cadherin dependent adhesion restricted the mobility of EGFR-CFP in the plasma membrane and eliminated high affinity EGF and IGF-1 binding sites, thus impairing the ability of the ligands to activate their cognate receptors. The results indicated that negative regulation of receptor tyrosine kinases by their soluble ligands is physiologic, specific, and adhesion-dependent. Since receptor tyrosine kinases have been implicated in multiple cellular processes, including nutrition, growth, and differentiation, the data imply that E-cadherin can regulate these processes. Abrogation of receptor tyrosine kinase regulation may also contribute to the frequent silencing of E-cadherin in tumors.