PTPN12/PTP-PEST Regulates Phosphorylation-Dependent Ubiquitination and Stability of Focal Adhesion Substrates in Invasive Glioblastoma Cells.
PTPN12/PTP-PEST Regulates Phosphorylation-Dependent Ubiquitination and Stability of Focal Adhesion Substrates in Invasive Glioblastoma Cells.
复制标题
PTPN12/PTP-PEST调节侵入性胶质母细胞瘤细胞中局部粘附底物的磷酸化依赖性泛素化和稳定性。
DOI：
10.1158/0008-5472.can-18-0085
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发表时间：
2018-07-15
期刊：
影响因子：
11.2
通讯作者：
McCarty JH
中科院分区：
文献类型：
--
作者：
Chen Z;Morales JE;Guerrero PA;Sun H;McCarty JH
胶质母细胞瘤（GBM）是一种侵袭性脑癌，肿瘤细胞从原发肿块中扩散，逃避手术切除，并总是引起致命的复发性病变。在这里，我们报告，PTP-PEST，细胞质蛋白酪氨酸磷酸酶，控制GBM细胞的侵袭，通过物理桥接的粘着斑蛋白Crk相关的底物（Cas）的valosin包含蛋白（Vcp），ATP依赖性蛋白分离酶，选择性地提取泛素化的蛋白质从多蛋白复合物和目标降解通过泛素蛋白酶体系统。Cas和Vcp都是PTP-PEST的底物，Vcp中酪氨酸805（Y805）的磷酸化状态影响粘着斑中Cas的亲和力并控制泛素化水平和蛋白质稳定性。干扰PTP-PEST介导的Cas和Vcp磷酸化导致体外和临床前小鼠模型中GBM细胞侵袭性生长的改变。总的来说，这些数据揭示了一种新的调控机制，涉及PTP-PEST，Vcp，和Cas的动态平衡磷酸化依赖的泛素化的关键局灶性蛋白参与GBM细胞侵袭。
Glioblastoma (GBM) is an invasive brain cancer with tumor cells that disperse from the primary mass, escaping surgical resection and invariably giving rise to lethal recurrent lesions. Here we report that PTP-PEST, a cytoplasmic protein tyrosine phosphatase, controls GBM cell invasion by physically bridging the focal adhesion protein Crk-associated substrate (Cas) to valosin containing protein (Vcp), an ATP-dependent protein segregase that selectively extracts ubiquitinated proteins from multiprotein complexes and targets them for degradation via the ubiquitin proteasome system. Both Cas and Vcp are substrates for PTP-PEST, with the phosphorylation status of tyrosine 805 (Y805) in Vcp impacting affinity for Cas in focal adhesions and controlling ubiquitination levels and protein stability. Perturbing PTP-PEST-mediated phosphorylation of Cas and Vcp led to alterations in GBM cell invasive growth in vitro and in pre-clinical mouse models. Collectively, these data reveal a novel regulatory mechanism involving PTP-PEST, Vcp, and Cas that dynamically balances phosphorylation-dependent ubiquitination of key focal proteins involved in GBM cell invasion.