Wounding Sheets of Epithelial Cells Activates the Epidermal Growth Factor Receptor through Distinct Short- and Long-Range Mechanisms
Wounding Sheets of Epithelial Cells Activates the Epidermal Growth Factor Receptor through Distinct Short- and Long-Range Mechanisms
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DOI：
10.1091/mbc.e08-01-0097
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发表时间：
2008-11-01
影响因子：
3.3
通讯作者：
Klarlund, Jes K.
中科院分区：
文献类型：
--
作者：
Block, Ethan R.;Klarlund, Jes K.
创伤上皮细胞诱导表皮生长因子受体（EGFR）的活化，这是诱导运动性所绝对需要的。ATP在受伤后从细胞中释放出来;它与细胞表面的嘌呤能受体结合，随后EGFR被激活。外源性ATP激活磷脂酶D，我们在这里表明，ATP激活EGFR通过磷脂酶D2亚型。EGFR在远离伤口（> 0.3cm）的细胞中被激活，这是由细胞外ATP的扩散介导的，因为在远离伤口的距离处的激活通过用腺苷三磷酸双磷酸酶消除培养基中的ATP而被消除。与此形成鲜明对比的是，伤口附近EGFR的激活对腺苷三磷酸双磷酸酶不敏感。延时显微镜显示，细胞在伤口边缘附近表现出增加的运动性;这种运动性的增加对腺苷三磷酸双磷酸酶不敏感，并且腺苷三磷酸双磷酸酶不能检测到抑制上皮片中伤口的愈合。这种新的ATP/PLD 2非依赖性途径通过配体释放的反式激活过程激活EGFR，并且它涉及Src激酶家族成员的信号传导。我们的结论是，创伤激活两个不同的信号通路，诱导表皮生长因子受体激活和促进愈合的伤口上皮细胞。一种途径通过释放ATP在离伤口一定距离处发出信号，另一种途径在局部起作用并且不依赖于ATP信号。
Wounding epithelia induces activation of the epidermal growth factor receptor (EGFR), which is absolutely required for induction of motility. ATP is released from cells after wounding; it binds to purinergic receptors on the cell surface, and the EGFR is subsequently activated. Exogenous ATP activates phospholipase D, and we show here that ATP activates the EGFR through the phospholipase D2 isoform. The EGFR is activated in cells far (> 0.3 cm) from wounds, which is mediated by diffusion of extracellular ATP because activation at a distance from wounds is abrogated by eliminating ATP in the medium with apyrase. In sharp contrast, activation of the EGFR near wounds is not sensitive to apyrase. Time-lapse microscopy revealed that cells exhibit increased motilities near edges of wounds; this increase in motility is not sensitive to apyrase, and apyrase does not detectably inhibit healing of wounds in epithelial sheets. This novel ATP/PLD2-independent pathway activates the EGFR by a transactivation process through ligand release, and it involves signaling by a member of the Src family of kinases. We conclude that wounding activates two distinct signaling pathways that induce EGFR activation and promote healing of wounds in epithelial cells. One pathway signals at a distance from wounds through release of ATP, and another pathway acts locally and is independent on ATP signaling.