E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner.
E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner.
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DOI：
10.1083/jcb.153.5.1049
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发表时间：
2001-05-28
期刊：
影响因子：
--
通讯作者：
Gumbiner BM
中科院分区：
文献类型：
--
作者：
Gottardi CJ;Wong E;Gumbiner BM
E - 钙黏蛋白是一种肿瘤抑制蛋白，在细胞 - 细胞黏附中具有明确的作用。黏附可通过物理连接细胞或促进其他近分泌信号传导事件来促进肿瘤抑制。或者，E - 钙黏蛋白的肿瘤抑制活性可能源于结合并拮抗β - 连环蛋白的核信号传导功能，β - 连环蛋白是一种已知的原癌基因。为了区分依赖黏附的机制与依赖β - 连环蛋白信号传导的机制，在SW480结直肠肿瘤细胞系中表达了嵌合钙黏蛋白构建体。野生型E - 钙黏蛋白的表达显著抑制该细胞系的生长。所有具有细胞质结构域的β - 连环蛋白结合区域的构建体都保留了生长抑制活性，但具有黏附活性但缺乏β - 连环蛋白结合区域的E - 钙黏蛋白构建体则没有。这种生长抑制与β - 连环蛋白/T细胞因子（TCF）报告基因活性的降低相关。重要的是，直接抑制β - 连环蛋白/TCF信号传导可抑制SW480细胞的生长，并且E - 钙黏蛋白的生长抑制活性可通过组成型激活形式的TCF来挽救。因此，E - 钙黏蛋白的生长抑制活性不依赖于黏附，而是源于对β - 连环蛋白/TCF信号通路的抑制，这表明E - 钙黏蛋白表达的缺失可导致人类癌症中该通路的上调。E - 钙黏蛋白介导的生长抑制并不伴随着细胞质和细胞核中β - 连环蛋白的总体耗竭。这似乎是由于SW480细胞中存在大量的细胞质β - 连环蛋白库，其对钙黏蛋白结合和TCF结合均不敏感。因此，一小部分可结合TCF的β - 连环蛋白（即具有转录活性的部分）可通过E - 钙黏蛋白的表达被选择性地耗竭。细胞质中功能不同的β - 连环蛋白库的存在表明，除了控制其积累水平外，还存在调节β - 连环蛋白信号传导的机制。
E-cadherin is a tumor suppressor protein with a well-established role in cell–cell adhesion. Adhesion could contribute to tumor suppression either by physically joining cells or by facilitating other juxtacrine signaling events. Alternatively, E-cadherin tumor suppressor activity could result from binding and antagonizing the nuclear signaling function of β-catenin, a known proto-oncogene. To distinguish between an adhesion- versus a β-catenin signaling–dependent mechanism, chimeric cadherin constructs were expressed in the SW480 colorectal tumor cell line. Expression of wild-type E-cadherin significantly inhibits the growth of this cell line. Growth inhibitory activity is retained by all constructs that have the β-catenin binding region of the cytoplasmic domain but not by E-cadherin constructs that exhibit adhesive activity, but lack the β-catenin binding region. This growth suppression correlates with a reduction in β-catenin/T cell factor (TCF) reporter gene activity. Importantly, direct inhibition of β-catenin/TCF signaling inhibits the growth of SW480 cells, and the growth inhibitory activity of E-cadherin is rescued by constitutively activated forms of TCF. Thus, the growth suppressor activity of E-cadherin is adhesion independent and results from an inhibition of the β-catenin/TCF signaling pathway, suggesting that loss of E-cadherin expression can contribute to upregulation of this pathway in human cancers. E-cadherin–mediated growth suppression was not accompanied by overall depletion of β-catenin from the cytosol and nucleus. This appears to be due to the existence of a large pool of cytosolic β-catenin in SW480 cells that is refractory to both cadherin binding and TCF binding. Thus, a small pool of β-catenin that can bind TCF (i.e., the transcriptionally active pool) can be selectively depleted by E-cadherin expression. The existence of functionally distinct pools of cytosolic β-catenin suggests that there are mechanisms to regulate β-catenin signaling in addition to controlling its level of accumulation.
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DOI：
10.1083/jcb.135.2.487
发表时间：
1996-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Brieher WM;Yap AS;Gumbiner BM
通讯作者：
Gumbiner BM
影响因子：
56.9
作者：
Behrens, J;Jerchow, BA;Birchmeier, W
通讯作者：
Birchmeier, W
影响因子：
8.8
作者：
de Both NJ;Vermey M;Dinjens WN;Bosman FT
通讯作者：
Bosman FT
影响因子：
64.5
作者：
HEASMAN, J;CRAWFORD, A;WYLIE, C
通讯作者：
WYLIE, C
影响因子：
9.2
作者：
Hart, MJ;de los Santos, R;Polakis, P
通讯作者：
Polakis, P