Cathepsin H Mediates the Processing of Talin and Regulates Migration of Prostate Cancer Cells
Cathepsin H Mediates the Processing of Talin and Regulates Migration of Prostate Cancer Cells
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DOI：
10.1074/jbc.m112.436394
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发表时间：
2013-01-25
影响因子：
4.8
通讯作者：
Kos, Janko
中科院分区：
文献类型：
--
作者：
Jevnikar, Zala;Rojnik, Matija;Kos, Janko
细胞骨架蛋白talin是一种肌动蛋白和β-整联蛋白尾部结合蛋白，通过促进整联蛋白活化和粘着斑形成在细胞迁移中起重要作用。在这里，我们表明，塔林是一个底物的组织蛋白酶H（CtsH），溶酶体半胱氨酸蛋白酶具有很强的氨肽酶活性。纯化的活性CtsH依次切割代表塔林素F0头部结构域的N末端的合成肽。还在转移性PC-3前列腺癌细胞系中测定了CtsH对talin的加工，该细胞系表现出CtsH表达增加。通过特异性抑制剂或siRNA介导的沉默减弱CtsH氨肽酶活性显著降低PC-3细胞在纤连蛋白上的迁移和通过Matrigel的侵袭。我们发现，在迁移PC-3细胞，CtsH与塔林共定位在局灶性粘连。此外，特异性抑制CtsH增加PC-3细胞上α（v）β（3）-整合素的活化。我们建议，CtsH介导的处理塔林可能会促进癌细胞的进展，通过影响整合素的激活和粘附强度。
The cytoskeletal protein talin, an actin-and beta-integrin tail-binding protein, plays an important role in cell migration by promoting integrin activation and focal adhesion formation. Here, we show that talin is a substrate for cathepsin H (CtsH), a lysosomal cysteine protease with a strong aminopeptidase activity. Purified active CtsH sequentially cleaved a synthetic peptide representing the N terminus of the talin F0 head domain. The processing of talin by CtsH was determined also in the metastatic PC-3 prostate cancer cell line, which exhibits increased expression of CtsH. The attenuation of CtsH aminopeptidase activity by a specific inhibitor or siRNA-mediated silencing significantly reduced the migration of PC-3 cells on fibronectin and invasion through Matrigel. We found that in migrating PC-3 cells, CtsH was co-localized with talin in the focal adhesions. Furthermore, specific inhibition of CtsH increased the activation of alpha(v)beta(3)-integrin on PC-3 cells. We propose that CtsH-mediated processing of talin might promote cancer cell progression by affecting integrin activation and adhesion strength.