Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx
Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx
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DOI：
10.1091/mbc.e06-01-0014
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发表时间：
2007-01-01
影响因子：
3.3
通讯作者：
Blobel, Carl P.
中科院分区：
文献类型：
--
作者：
Horiuchi, Keisuke;Le Gall, Sylvain;Blobel, Carl P.
通过表皮生长因子受体（EGFR）的信号传导（其在发育和疾病如癌症中具有关键作用）由其膜系配体的蛋白水解脱落调节。因此，EGFR配体的脱落酶是EGFR途径中的关键信号传导开关。在这里，我们确定了亚当斯（一种去整合素和金属蛋白酶）可以脱落各种EGFR配体，我们分析了两种常用的刺激，佛波醇酯和钙离子内流的EGFR配体脱落的调节。佛波酯主要激活ADAM17，从而触发EGFR配体从晚期分泌途径隔室的脱落爆发。钙内流刺激ADAM 10，需要其胞质结构域。然而，钙流入刺激脱落的转化生长因子a和双调蛋白不需要ADAM 17，即使ADAM 17是必不可少的佛波酯刺激脱落的这些EGFR配体。这项研究提供了新的洞察机制负责EGFR配体释放，因此EGFR信号，并表明，失调EGFR配体脱落可能是由增加表达的组成型活性sheddases或激活不同的sheddases由不同的刺激。
Signaling via the epidermal growth factor receptor (EGFR), which has critical roles in development and diseases such as cancer, is regulated by proteolytic shedding of its membrane-tethered ligands. Sheddases for EGFR-ligands are therefore key signaling switches in the EGFR pathway. Here, we determined which ADAMs (a disintegrin and metalloprotease) can shed various EGFR-ligands, and we analyzed the regulation of EGFR-ligand shedding by two commonly used stimuli, phorbol esters and calcium influx. Phorbol esters predominantly activate ADAM17, thereby triggering a burst of shedding of EGFR-ligands from a late secretory pathway compartment. Calcium influx stimulates ADAM10, requiring its cytoplasmic domain. However, calcium influx-stimulated shedding of transforming growth factor a and amphiregulin does not require ADAM17, even though ADAM17 is essential for phorbol ester-stimulated shedding of these EGFR-ligands. This study provides new insight into the machinery responsible for EGFR-ligand release and thus EGFR signaling and demonstrates that dysregulated EGFR-ligand shedding may be caused by increased expression of constitutively active sheddases or activation of different sheddases by distinct stimuli.