Wnt信號通路是一個復雜的蛋白質(zhì)作用網(wǎng)絡，其功能最常見于胚胎發(fā)育和癌癥,，但也參與成年動物的正常生理過程,。
經(jīng)典Wnt通路描述當Wnt蛋白于細胞表面Frizzled受體家族結(jié)合后的一系列反應，包括Dishevelled受體家族蛋白質(zhì)的激活及最終細胞核內(nèi)β-catenin水平的變化。 Dishevelled (DSH) 是細胞膜相關Wnt受體復合物的關鍵成分,，它與Wnt結(jié)合后被激活,，并抑制下游蛋白質(zhì)復合物，包括axin,、GSK-3,、與APC蛋白。axin/GSK-3/APC 復合體可促進細胞內(nèi)信號分子β-catenin的降解,。當“β-catenin 降解復合物”被抑制后,，胞漿內(nèi)的β-catenin得以穩(wěn)定存在，部分 β-catenin進入細胞核與TCF/LEF轉(zhuǎn)錄因子家族作用并促進特定基因的表達,。
Wnt信號通路誘導β-catenin/lymphoid的增強因子轉(zhuǎn)錄因子,。Wnt信號通路在各種癌癥類型中都處于激活狀態(tài)，Wnt激活后通過促進腫瘤細胞遷移侵襲,，加劇腫瘤的轉(zhuǎn)移,。在黑色素瘤中，Wnt/β-catenin信號通路也處于激活狀態(tài),，但在細胞核內(nèi)β-catenin的存在似乎并不與這些腫瘤的侵襲性相關,。
最新研究發(fā)現(xiàn)不同于刺激其他類型腫瘤細胞的遷移侵襲的陽性促進作用，β-catenin信號會導致黑色素細胞的遷移下降,。在體內(nèi),，β-連環(huán)素信號降低黑素細胞的遷移，β-catenin的抑制遷移作用依賴于MITF-M和CSK,，MITF-M是黑色素細胞的關鍵轉(zhuǎn)錄因子,，CSK是一個Src抑制劑。盡管減少遷移,，在NRAS誘導的黑色素瘤小鼠模型β-catenin信號通路卻促進肺轉(zhuǎn)移,。（生物谷：Bioon.com）
doi:10.1038/onc.2012.229
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Beta-catenin inhibits melanocyte migration but induces melanoma metastasis
S J Gallagher, F Rambow, M Kumasaka, D Champeval, A Bellacosa, V Delmas, and L Larue
The canonical Wnt signalling pathway induces the β-catenin/lymphoid enhancer factor transcription factors. It is activated in various cancers, most characteristically carcinomas, in which it promotes metastatic spread by increasing migration and/or invasion. The Wnt/β-catenin signalling pathway is frequently activated in melanoma, but the presence of β-catenin in the nucleus does not seem to be a sign of aggressiveness in these tumours. We found that, unlike its positive role in stimulating migration and invasion of carcinoma cells, β-catenin signalling decreased the migration of melanocytes and melanoma cell lines. In vivo, β-catenin signalling in melanoblasts reduced the migration of these cells, causing a white belly-spot phenotype. The inhibition by β-catenin of migration was dependent on MITF-M, a key transcription factor of the melanocyte lineage, and CSK, an Src-inhibitor. Despite reducing migration, β-catenin signalling promoted lung metastasis in the NRAS-driven melanoma murine model. Thus, β-catenin may have conflicting roles in the metastatic spread of melanoma, repressing migration while promoting metastasis. These results highlight that metastasis formation requires a series of successful cellular processes, any one of which may not be optimally efficient.
