Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2011 Jan 7;286(1):79-90. doi: 10.1074/jbc.M110.169821. Epub 2010 Oct 18.
Epithelial cells are dependent on extracellular matrix (ECM) attachment for maintenance of metabolic activity and suppression of apoptosis. Here we show that loss of ECM attachment causes down-regulation of epidermal growth factor receptor (EGFR) and β1 integrin protein and mRNA expression and that ErbB2, which is amplified in 25% of breast tumors, reverses these effects of ECM deprivation. ErbB2 rescue of β1 integrin mRNA and protein in suspended cells is dependent on EGFR, however, the rescue of EGFR expression does not require β1 integrin. We show that there is a significant decrease in the stability of EGFR in ECM-detached cells that is reversed by ErbB2 overexpression. Rescue of both EGFR and β1 integrin protein by ErbB2 is dependent on Erk activity and induction of its downstream target Sprouty2, a protein known to regulate EGFR protein stability. Interestingly, expression of EGFR and β1 integrin protein is more dependent on Erk/Sprouty2 in ECM-detached ErbB2-overexpressing cells when compared with ECM-attached cells. These results provide further insight into the ErbB2-driven anchorage independence of tumor cells and provide a new mechanism for regulation of EGFR and β1 integrin expression in ECM-detached cells.
上皮细胞依赖细胞外基质（ECM）附着来维持代谢活性和抑制细胞凋亡。在这里，我们表明 ECM 附着的丧失导致表皮生长因子受体（EGFR）和β1 整合素蛋白和 mRNA 表达下调，而在 25%的乳腺癌中扩增的 ErbB2 逆转了 ECM 剥夺的这些效应。悬浮细胞中 ErbB2 对β1 整合素 mRNA 和蛋白的挽救依赖于 EGFR，但 EGFR 表达的挽救不需要β1 整合素。我们表明，在 ECM 分离的细胞中 EGFR 的稳定性显著降低，而 ErbB2 的过表达可以逆转这种情况。ErbB2 对 EGFR 和β1 整合素蛋白的挽救依赖于 Erk 活性及其下游靶标 Sprouty2 的诱导，Sprouty2 是一种已知调节 EGFR 蛋白稳定性的蛋白质。有趣的是，与 ECM 附着细胞相比，在 ECM 分离的 ErbB2 过表达细胞中，EGFR 和β1 整合素蛋白的表达对 Erk/Sprouty2 的依赖性更大。这些结果为 ErbB2 驱动的肿瘤细胞锚定独立性提供了更深入的了解，并为 ECM 分离细胞中 EGFR 和β1 整合素表达的调节提供了新的机制。
