IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity
IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity
复制标题
DOI：
10.3390/ijms21061968
复制
发表时间：
2020-03-01
影响因子：
5.6
通讯作者：
Ye, Yan
中科院分区：
文献类型：
--
作者：
Xu, Liang;Shao, Yuling;Ye, Yan
先前的研究表明，在胃癌（GC）中，含Src同源2的肌醇5-磷酸酶2（SHIP 2）的表达减少及其肿瘤抑制作用。然而，SHIP 2在GC细胞迁移和侵袭中的确切作用仍不清楚。在这里，IQ基序含有GTP酶激活蛋白2（IQGAP 2）作为SHIP 2结合伴侣，筛选和鉴定的免疫共沉淀和质谱研究。虽然IQGAP 2在GC细胞中普遍表达，但IQGAP 2和SHIP 2共定位于GC细胞的细胞质中，并且通过IQGAP 2与SHIP 2的PRD和SAM结构域的结合证实了这种物理关联。SHIP 2或IQGAP 2的敲低通过抑制SHIP 2磷酸酶活性、激活Akt并随后增加上皮-间充质转化（EMT）来促进细胞迁移和侵袭。此外，在SHIP 2过表达的GC细胞中，IQGAP 2的敲低逆转了SHIP 2诱导对细胞迁移和侵袭的抑制，这与升高的SHIP 2磷酸酶活性的抑制有关。此外，SHIP 2的PRD和SAM结构域的缺失消除了相互作用，并恢复了细胞的迁移和侵袭。总之，这些结果表明IQGAP 2与SHIP 2相互作用，导致SHIP 2磷酸酶活性增加，从而通过Akt失活和EMT减少来抑制GC细胞的迁移和侵袭。
Previous studies have shown reduced expression of Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) and its tumor-suppressive role in gastric cancer (GC). However, the precise role of SHIP2 in the migration and invasion of GC cells remains unclear. Here, an IQ motif containing the GTPase-activating protein 2 (IQGAP2) as a SHIP2 binding partner, was screened and identified by co-immunoprecipitation and mass spectrometry studies. While IQGAP2 ubiquitously expressed in GC cells, IQGAP2 and SHIP2 co-localized in the cytoplasm of GC cells, and this physical association was confirmed by the binding of IQGAP2 to PRD and SAM domains of SHIP2. The knockdown of either SHIP2 or IQGAP2 promoted cell migration and invasion by inhibiting SHIP2 phosphatase activity, activating Akt and subsequently increasing epithelial-mesenchymal transition (EMT). Furthermore, knockdown of IQGAP2 in SHIP2-overexpressing GC cells reversed the inhibition of cell migration and invasion by SHIP2 induction, which was associated with the suppression of elevated SHIP2 phosphatase activity. Moreover, the deletion of PRD and SAM domains of SHIP2 abrogated the interaction and restored cell migration and invasion. Collectively, these results indicate that IQGAP2 interacts with SHIP2, leading to the increment of SHIP2 phosphatase activity, and thereby inhibiting the migration and invasion of GC cells via the inactivation of Akt and reduction in EMT.