Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively
Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively
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DOI：
10.1038/sj.onc.1209287
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发表时间：
2006-04-01
期刊：
影响因子：
8
通讯作者：
Yu, Q
中科院分区：
文献类型：
--
作者：
Liu, YJ;Xu, Y;Yu, Q
具有血小板反应蛋白基序的去整合素和金属蛋白酶-1（ADAMTS-1）的确切作用及其参与肿瘤转移的潜在机制尚未确定。我们现在已经证明ADAMTS-1的过表达促进TA 3乳腺癌和刘易斯肺癌细胞的肺转移，并且ADAMTS-1的蛋白酶死亡突变体（ADAMTS-1 E/Q）抑制它们的转移，这表明ADAMTS-1的促转移活性需要其金属蛋白酶活性。ADAMTS-1在这些细胞中的过表达促进肿瘤血管生成和侵袭，肝素结合表皮生长因子（EGF）和双调蛋白（AR）的跨膜前体脱落，以及EGF受体和ErbB-2的激活，而ADAMTS-1 E/Q的过表达抑制这些事件。此外，我们发现，ADAMTS-1进行自我蛋白水解切割，以产生NH 2-和COOH-末端切割片段，其中至少有一个凝血酶敏感蛋白I型样基序和过表达的NH 2-末端ADAMTS-1片段和COOH-末端ADAMTS-1片段可以抑制肺肿瘤转移。这些片段也抑制Erk 1/2激酶激活诱导的可溶性肝素结合EGF和AR。总之，我们的研究结果表明，ADAMTS-1的蛋白水解状态决定其对肿瘤转移的影响，ADAMTS-1 E/Q和ADAMTS-1片段可能通过负调节可溶性肝素结合EGF和AR的可用性和活性来抑制肿瘤转移。
The exact role of a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) and the underlying mechanism of its involvement in tumor metastasis have not been established. We have now demonstrated that overexpression of ADAMTS-1 promotes pulmonary metastasis of TA3 mammary carcinoma and Lewis lung carcinoma cells and that a proteinase-dead mutant of ADAMTS-1 (ADAMTS-1E/Q) inhibits their metastasis, indicating that the prometastatic activity of ADAMTS-1 requires its metalloproteinase activity. Overexpression of ADAMTS-1 in these cells promoted tumor angiogenesis and invasion, shedding of the transmembrane precursors of heparin-binding epidermal growth factor (EGF) and amphiregulin (AR), and activation of the EGF receptor and ErbB-2, while overexpression of ADAMTS-1E/Q inhibited these events. Furthermore, we found that ADAMTS-1 undergoes auto-proteolytic cleavage to generate the NH2- and COOH-terminal cleavage fragments containing at least one thrombospondin-type-I-like motif and that overexpression of the NH2- terminal ADAMTS-1 fragment and the COOH-terminal ADAMTS-1 fragment can inhibit pulmonary tumor metastasis. These fragments also inhibited Erk1/2 kinase activation induced by soluble heparin-binding EGF and AR. Taken together, our results suggest that the proteolytic status of ADAMTS-1 determines its effect on tumor metastasis, and that the ADAMTS-1E/Q and the ADAMTS-1 fragments likely inhibit tumor metastasis by negatively regulating the availability and activity of soluble heparin-binding EGF and AR.