Proteolytic cleavage of protein tyrosine phosphatase mu regulates glioblastoma cell migration.
Proteolytic cleavage of protein tyrosine phosphatase mu regulates glioblastoma cell migration.
复制标题
DOI：
10.1158/0008-5472.can-09-0863
复制
发表时间：
2009-09-01
期刊：
影响因子：
11.2
通讯作者：
Brady-Kalnay SM
中科院分区：
文献类型：
--
作者：
Burgoyne AM;Phillips-Mason PJ;Burden-Gulley SM;Robinson S;Sloan AE;Miller RH;Brady-Kalnay SM
多形性胶质母细胞瘤（GBM）是最常见的恶性原发性脑肿瘤，带来了重大的疾病负担。 GBM肿瘤细胞广泛分散在整个脑实质中，非常需要肿瘤特异性药物靶点和药理制剂来抑制细胞迁移和分散。受体蛋白酪氨酸磷酸酶 mu (PTPmu) 是一种同源性细胞粘附分子。全长形式的 PTPmu 在人胶质母细胞瘤中下调。在这份手稿中，全长 PTPmu 的过度表达被证明可以抑制胶质母细胞瘤细胞的迁移和存活。此外，蛋白水解裂解被证明是胶质母细胞瘤细胞中 PTPmu 下调的机制。 PTPmu 的蛋白水解产生一系列蛋白水解片段，包括易位至细胞核的可溶性催化胞内结构域 (ICD) 片段。在人胶质母细胞瘤中仅检测到蛋白水解的 PTPmu 片段。 shRNA 介导的 PTPmu 片段下调会降低胶质母细胞瘤细胞的迁移和存活。 PTPmu 功能的肽抑制剂可阻断片段诱导的胶质母细胞瘤细胞迁移，这可能在 GBM 治疗中具有治疗价值。这些数据表明，蛋白水解导致细胞表面 PTPmu 损失，产生催化活性 PTPmu 片段，有助于胶质母细胞瘤细胞的迁移和存活。
Glioblastoma multiforme (GBM), the most common malignant primary brain tumor, represents a significant disease burden. GBM tumor cells disperse extensively throughout the brain parenchyma, and the need for tumor-specific drug targets and pharmacological agents to inhibit cell migration and dispersal is great. The receptor protein tyrosine phosphatase mu (PTPmu) is a homophilic cell adhesion molecule. The full-length form of PTPmu is downregulated in human glioblastoma. In this manuscript, overexpression of full-length PTPmu is demonstrated to suppress migration and survival of glioblastoma cells. Additionally, proteolytic cleavage is shown to be the mechanism of PTPmu downregulation in glioblastoma cells. Proteolysis of PTPmu generates a series of proteolytic fragments including a soluble catalytic intracellular domain (ICD) fragment that translocates to the nucleus. Only proteolyzed PTPmu fragments are detected in human glioblastomas. shRNA-mediated downregulation of PTPmu fragments decreases glioblastoma cell migration and survival. A peptide inhibitor of PTPmu function blocks fragment-induced glioblastoma cell migration, which may prove to be of therapeutic value in GBM treatment. These data suggest that loss of cell surface PTPmu by proteolysis generates catalytically active PTPmu fragments that contribute to migration and survival of glioblastoma cells.