E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions
E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions
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DOI：
10.1091/mbc.e06-04-0348
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发表时间：
2007-06-01
影响因子：
3.3
通讯作者：
Gumbiner, Barry M.
中科院分区：
文献类型：
--
作者：
Perrais, Michael;Chen, Xiao;Gumbiner, Barry M.
E-钙粘附素的作用导致密度依赖的接触性抑制细胞生长。由于钙粘附素控制细胞接触、细胞骨架组织和许多其他类型细胞相互作用的建立的整体状态，因此E-钙粘附素是否直接传递生长抑制信号仍是未知的。为了解决这个问题，我们通过将具有功能活性的重组E-钙粘蛋白连接到微球上，选择性地在分离的上皮细胞表面形成E-钙粘蛋白亲和键。我们发现E-钙粘素单独结扎降低了细胞进入S期的频率，表明E-钙粘素结扎直接传递生长抑制信号。E-钙粘附素与ss-catenin结合是细胞生长抑制所必需的，但ss-catenin/T细胞因子转录活性不参与同源结合导致的生长抑制。生长抑制不需要E-钙粘附素与p120-连环素结合，也不需要ss-连环素与α-连环素结合，从而不需要肌动蛋白细胞骨架。E-钙粘素结扎也通过ss-连环蛋白依赖的机制抑制表皮生长因子(EGF)受体介导的生长信号。它不影响EGF受体的自磷酸化或ERK的激活，但抑制Tyr845的转磷酸化以及信号转导和转录激活子5的激活。因此，不依赖于其他细胞接触的E-钙粘素亲性结合直接通过ss-连环蛋白依赖的机制抑制生长因子受体的选择性信号功能来转导生长抑制。
E-cadherin function leads to the density-dependent contact inhibition of cell growth. Because cadherins control the overall state of cell contact, cytoskeletal organization, and the establishment of many other kinds of cell interactions, it remains unknown whether E-cadherin directly transduces growth inhibitory signals. To address this question, we have selectively formed E-cadherin homophilic bonds at the cell surface of isolated epithelial cells by using functionally active recombinant E-cadherin protein attached to microspheres. We find that E-cadherin ligation alone reduces the frequency of cells entering the S phase, demonstrating that E-cadherin ligation directly transduces growth inhibitory signals. E-cadherin binding to ss-catenin is required for cell growth inhibition, but ss-catenin/T-cell factor transcriptional activity is not involved in growth inhibition resulting from homophilic binding. Neither E-cadherin binding to p120-catenin nor ss-catenin binding to alpha-catenin, and thereby the actin cytoskeleton, is required for growth inhibition. E-cadherin ligation also inhibits epidermal growth factor (EGF) receptor-mediated growth signaling by a ss-catenin- dependent mechanism. It does not affect EGF receptor autophosphorylation or activation of ERK, but it inhibits transphosphorylation of Tyr845 and activation of signal transducers and activators of transcription 5. Thus, E-cadherin homophilic binding independent of other cell contacts directly transduces growth inhibition by a ss-catenin- dependent mechanism that inhibits selective signaling functions of growth factor receptors.