Tartrate–resistant acid phosphatase (TRAP/ ACP5) belongs to the binuclear metallophosphatase family and is present in two isoforms. The primary translation product is an uncleaved TRAP 5a isoform with low phosphatase activity. TRAP 5a can be post-translationally processed to a cleaved TRAP 5b isoform with high phosphatase activity by e.g. cysteine proteinases, such as Cathepsin K (CtsK). The relevance of the phosphatase activity of TRAP 5b has been demonstrated for proliferation, migration and invasion of cancer cells. TRAP-overexpressing MDA-MB-231 breast cancer cells displayed higher levels of TRAP 5a and efficient processing of TRAP 5a to TRAP 5b protein, but no changes in levels of CtsK when compared to mock-transfected cells. In TRAP-overexpressing cells colocalization of TRAP 5a and proCtsK was augmented, providing a plausible mechanism for generation of TRAP 5b. CtsK expression has been associated with cancer progression and has been pharmacologically targeted in several clinical studies. In the current study, CtsK inhibition with MK-0822/Odanacatib did not abrogate the formation of TRAP 5b, but reversibly increased the intracellular levels of a N-terminal fragment of TRAP 5b and reduced secretion of TRAP 5a reversibly. However, MK-0822 treatment neither altered intracellular TRAP activity nor TRAP-dependent cell migration, suggesting involvement of additional proteases in proteolytic processing of TRAP 5a. Notwithstanding, CtsK was shown to be colocalized with TRAP and to be involved in the regulation of secretion of TRAP 5a in a breast cancer cell line, while it still was not essential for processing of TRAP 5a to TRAP 5b isoform. In cancer cells multiple proteases are involved in cleaving TRAP 5a to high-activity phosphatase TRAP 5b. However, CtsK-inhibiting treatment was able to reduce secretion TRAP 5a from TRAP-overexpressing cancer cells.

中文翻译：

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组织蛋白酶K调节过表达TRAP的MDA-MB-231乳腺癌细胞中抗酒石酸酸性磷酸酶（TRAP）的定位和分泌

耐酒石酸酸性磷酸酶（TRAP / ACP5）属于双核金属磷酸酶家族，以两种亚型存在。主要翻译产物是具有低磷酸酶活性的未切割的TRAP 5a同工型。可以通过例如半胱氨酸蛋白酶，例如组织蛋白酶K（CtsK）将TRAP 5a翻译后加工成具有高磷酸酶活性的裂解的TRAP 5b同工型。已经证明TRAP 5b的磷酸酶活性与癌细胞的增殖，迁移和侵袭有关。与模拟转染的细胞相比，过表达TRAP的MDA-MB-231乳腺癌细胞显示出更高的TRAP 5a水平和有效的TRAP 5a到TRAP 5b蛋白加工能力，但是CtsK的水平没有变化。在过表达TRAP的细胞中，TRAP 5a和proCtsK的共定位增强了，提供了产生TRAP 5b的合理机制。CtsK的表达与癌症的进展有关，并且在一些临床研究中已被药理学靶向。在当前研究中，用MK-0822 / Odanacatib抑制CtsK并不能消除TRAP 5b的形成，但是可逆地增加了TRAP 5b N端片段的细胞内水平，并可逆地减少了TRAP 5a的分泌。但是，MK-0822处理既不会改变细胞内TRAP活性，也不会改变TRAP依赖性细胞迁移，提示其他蛋白酶参与了TRAP 5a的蛋白水解过程。尽管如此，已显示CtsK与TRAP共定位并参与乳腺癌细胞系中TRAP 5a分泌的调节，而对于将TRAP 5a加工成TRAP 5b同工型仍然不是必需的。在癌细胞中，多种蛋白酶参与将TRAP 5a切割成高活性磷酸酶TRAP 5b。然而，抑制CtsK的处理能够减少过表达TRAP的癌细胞的分泌TRAP 5a。