Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling
Src-induced de-regulation of E-cadherin in colon cancer cells requires integrin signalling
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DOI：
10.1038/ncb829
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发表时间：
2002-08-01
影响因子：
21.3
通讯作者：
Frame, MC
中科院分区：
文献类型：
--
作者：
Avizienyte, E;Wyke, AW;Frame, MC
尽管Src的表达和活性在结肠癌中经常升高（1-3），但非催化性Src同源性（SH）结构域过表达或催化活性增强的确切后果尚不清楚。我们发现，在KM12C结肠癌细胞中，Src活性升高导致粘附连接的成分，包括血管素，被重新分配到Src诱导的整合素粘附复合物中。具体来说，当细胞从含低水平钙的培养基切换到含高水平钙的培养基时，Src活性升高会阻碍细胞间接触的正常组装，e -钙粘蛋白仍然内化。相比之下，尽管Src的非催化结构域的表达升高足以诱导整合素-粘附复合物的组装，但它不会诱导e -钙粘蛋白相关的细胞间接触的破坏。令人惊讶的是，src诱导的E-cadherin定位中断需要特异性整合素信号传导，因为E-cadherin再分配被细胞-基质相互作用的丧失或α (v)或β(1)整合素亚基的抑制性抗体所阻断。此外，Src诱导的E-cadherin去调控需要整合素调控的focal adhesion kinase （FAK）在Src特异性位点上的磷酸化，这表明整合素诱导的信号与Src诱导的cadherin相关的粘附变化之间存在相互依存关系。
Although Src expression and activity are often elevated in colon cancer(1-3), the precise consequences of overexpression of the non-catalytic Src homology (SH) domains, or enhanced catalytic activity, are unknown. We show that, in KM12C colon cancer cells, elevated Src activity causes the components of adherens junctions, including vinculin, to be redistributed to Src-induced integrin-adhesion complexes. Specifically, elevated Src activity blocks proper assembly of cell-cell contacts after cells are switched from media containing a low level of calcium to media containing a high level of calcium, and E-cadherin remains internalized. In contrast, although elevated expression of the non-catalytic domains of Src is sufficient to induce assembly of integrin-adhesion complexes, it does not induce disorganization of E-cadherin-associated intercellular contacts. Surprisingly, Src-induced disruption of E-cadherin localization requires specific integrin signalling, because E-cadherin redistribution is blocked by loss of cell-matrix interaction, or by inhibitory antibodies to alpha(v) or beta(1) integrin subunits. Furthermore, phosphorylation of the integrin-regulated focal adhesion kinase (FAK) on Src-specific sites is required for Src-induced de-regulation of E-cadherin, demonstrating interdependence between integrin-induced signals and cadherin-associated adhesion changes induced by Src.