IGFBP5 induces cell adhesion, increases cell survival and inhibits cell migration in MCF-7 human breast cancer cells
IGFBP5 induces cell adhesion, increases cell survival and inhibits cell migration in MCF-7 human breast cancer cells
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DOI：
10.1242/jcs.092882
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发表时间：
2012-04-01
影响因子：
4
通讯作者：
Flint, David
中科院分区：
文献类型：
--
作者：
Sureshbabu, Angara;Okajima, Hiroshi;Flint, David
维持组织边界对于控制转移至关重要。我们描述了一种新的信号通路，其中上皮细胞破坏可以最小化，从而限制上皮间充质越界。这涉及从凋亡细胞释放胰岛素样生长因子（IGF）结合蛋白5（IGFBP 5），其增加上皮细胞在间充质而非上皮细胞外基质（ECM）上的粘附，并且涉及IGFBP 5和α 2 β 1整联蛋白的直接相互作用。IGFBP 5还在不存在α V β 3整联蛋白（玻连蛋白受体）的情况下再次通过α 2 β 1-整联蛋白依赖性作用诱导细胞粘附到玻连蛋白，表明IGFBP 5可以诱导在基质上的铺展，即使在不存在通常用于该过程的整联蛋白的情况下。使用IGFBP 5突变体，我们证明了这种效应是IGF独立的，但需要在IGFBP 5的C-末端的肝素结合结构域。一个截短的突变体只含有IGFBP 5的C-末端也诱导粘附。IGFBP 5诱导的粘附依赖于Cdc 42，并导致整合素连接激酶（ILK）和Akt的激活。与这些变化相一致，IGFBP 5促进了营养不良条件下细胞存活时间的延长，并降低了应激激活激酶p38 MAPK（MAPK 14）的磷酸化。而IGFBP 5增强粘附，它抑制细胞迁移，虽然这是不明显的使用截短的C-末端突变体，表明IGFBP 5对粘附和迁移的影响涉及不同的机制。我们预期这些对IGFBP 5的反应将降低细胞的转移潜力。
Maintenance of tissue boundaries is crucial for control of metastasis. We describe a new signalling pathway in which epithelial cell disruption can be minimised and thereby restricts epithelial-mesenchymal transgressions. This involves the release of insulin-like growth factor (IGF)-binding protein 5 (IGFBP5) from apoptotic cells, which increases the adhesion of epithelial cells on mesenchymal but not epithelial extracellular matrix (ECM), and involves the direct interaction of IGFBP5 and alpha 2 beta 1 integrins. IGFBP5 also induced cell adhesion to vitronectin in the absence of alpha V beta 3 integrin, the vitronectin receptor, again through an alpha 2 beta 1-integrin-dependent action, suggesting that IGFBP5 can induce spreading on matrices, even in the absence of the integrins normally used in this process. Using IGFBP5 mutants we demonstrate that the effect is IGF-independent but requires the heparin-binding domain in the C-terminus of IGFBP5. A truncated mutant containing only the C-terminal of IGFBP5 also induced adhesion. Adhesion induced by IGFBP5 was dependent on Cdc42 and resulted in activation of integrin-linked kinase (ILK) and Akt. Consistent with these changes, IGFBP5 facilitated prolonged cell survival in nutrient-poor conditions and decreased phosphorylation of the stress-activated kinase p38 MAPK (MAPK14). Whereas IGFBP5 enhanced adhesion, it inhibited cell migration, although this was not evident using the truncated C-terminal mutant, suggesting that effects of IGFBP5 on adhesion and migration involve different mechanisms. We anticipate that these responses to IGFBP5 would reduce the metastatic potential of cells.