A protease storm cleaves a cell-cell adhesion molecule in cancer: multiple proteases converge to regulate PTPmu in glioma cells.
A protease storm cleaves a cell-cell adhesion molecule in cancer: multiple proteases converge to regulate PTPmu in glioma cells.
复制标题
DOI：
10.1002/jcb.24824
复制
发表时间：
2014-09
影响因子：
4
通讯作者：
Brady-Kalnay SM
中科院分区：
文献类型：
--
作者：
Phillips-Mason PJ;Craig SE;Brady-Kalnay SM
细胞-细胞粘附分子PTPμ的裂解发生在人多形性胶质母细胞瘤脑肿瘤组织和胶质瘤细胞系中。PTPμ切割与胶质瘤细胞的体外细胞运动性和生长因子非依赖性存活有关。以前，PTPμ被证明在高尔基体中被弗林蛋白酶切割，产生膜相关的E-（细胞外）和P-（磷酸酶）亚基，并在质膜上被亚当斯和γ分泌酶复合物切割。我们还鉴定了脑肿瘤中额外的细胞外和细胞内PTPμ片段的存在。我们着手对癌细胞中PTPμ裂解进行生物化学分析。我们确定，除了弗林蛋白酶处理形式的PTPμ外，质膜上还存在一个200 kDa全长PTPμ的库，该库被ADAM直接切割，以产生更大脱落形式的PTPμ细胞外片段。值得注意的是，在神经胶质瘤细胞中，全长PTPμ也受到钙蛋白酶切割，这产生了在其他永生化细胞中未发现的新型PTPμ片段。我们还观察到癌细胞中糖基化和磷酸化的差异。我们的数据表明，额外的丝氨酸蛋白酶也有助于神经胶质瘤细胞中的PTPμ脱落。我们假设癌细胞中发生了“蛋白酶风暴”，由此多种蛋白酶会聚以减少质膜上细胞-细胞粘附分子的存在并产生具有独特生物学功能的蛋白质片段。因此，“蛋白酶风暴”可以促进肿瘤细胞的迁移和侵袭。
Cleavage of the cell-cell adhesion molecule, PTPμ, occurs in human glioblastoma multiforme brain tumor tissue and glioma cell lines. PTPμ cleavage is linked to increased cell motility and growth factor independent survival of glioma cells in vitro. Previously, PTPμ was shown to be cleaved by furin in the golgi to generate membrane associated E- (extracellular) and P- (phosphatase) subunits, and by ADAMs and the gamma secretase complex at the plasma membrane. We also identified the presence of additional extracellular and intracellular PTPμ fragments in brain tumors. We set out to biochemically analyze PTPμ cleavage in cancer cells. We determined that, in addition to the furin-processed form of PTPμ, a pool of 200 kDa full-length PTPμ exists at the plasma membrane that is cleaved directly by ADAM to generate a larger shed form of the PTPμ extracellular segment. Notably, in glioma cells, full-length PTPμ is also subject to calpain cleavage, which generates novel PTPμ fragments not found in other immortalized cells. We also observed glycosylation and phosphorylation differences in the cancer cells. Our data suggest that an additional serine protease also contributes to PTPμ shedding in glioma cells. We hypothesize that a “protease storm” occurs in cancer cells whereby multiple proteases converge to reduce the presence of cell-cell adhesion molecules at the plasma membrane and to generate protein fragments with unique biological functions. As a consequence, the “protease storm” could promote the migration and invasion of tumor cells.