IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity

Abstract

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.

LncRNA PDCD4-AS1 alleviates triple negative breast cancer by increasing expression of IQGAP2 via miR-10b-5p

“…Furthermore, we identified IQGAP2 as a downstream target of miR-10b-5p in TNBC cells. Recently, IQGAP2 has been reported as a tumor suppressor in many cancers including prostate cancer [33] , gastric cancer [34] and ovarian cancer [35] . Consistently, our findings showed that IQGAP2 was lowly expressed in TNBC cells and upregulated expression of IQGAP2 suppressed the malignant behaviors of TNBC cells.…”

Role of IQGAP1 in Carcinogenesis

“…In addition to IQGAP1, the IQGAP protein family includes IQGAP2 and IQGAP3, which are both structurally similar to IQGAP1, but are expressed in more limited types of organs [1,12]. The roles of these two proteins, particularly IQGAP3, in carcinogenesis, are less well understood, but the emerging picture is that, while IQGAP3 functions similarly to IQGAP1 as an oncogene, IQGAP2 may serve as a tumor suppressor [12,[81][82][83][84][85]. Further studies into how IQGAP2 and IQGAP3 contribute to cancer and how the IQGAP proteins compensate or coordinate with each other will shed more light on IQGAP-mediated carcinogenesis and related therapy designs.…”

Long non‐coding ribonucleic acid ATP2B1‐AS1 modulates endothelial permeability through regulating the miR‐4729–IQGAP2 axis in diabetic retinopathy

“…With respect to IQ motif-containing GTPase-activating protein 2 (IQGAP2), it functions as a scaffolding protein that regulates the cytoskeleton by juxtaposing Rho GTPase and Ca 2+ /calmodulin signals 26 . Low expression of IQGAP2 has been identified in ovarian cancer, prostate cancer, hepatocellular carcinoma and gastric cancer [27][28][29][30] , suggesting that IQGAP2 functions as a tumor suppressor. However, the IQGAP2 biological functions in DR are yet to be uncovered.…”