Abstract
The small GTPase Rac1 is thought to play an important role in cell migration and invasion. We have previously identified synaptojanin 2, a phosphoinositide phosphatase, as an effector of Rac1. Here, we show that small interfering RNA-mediated depletion of either Rac1 or synaptojanin 2 inhibits invasion of SNB19 and U87MG glioblastoma cells through Matrigel and rat brain slices. Depletion of Rac1 or synaptojanin 2 also inhibits migration of SNB19 and U87MG cells on glioma-derived extracellular matrix. In addition, we found that depletion of Rac1 or synaptojanin 2 inhibits the formation of lamellipodia and invadopodia, specialized membrane structures that are thought to be involved in extracellular matrix degradation. These results suggest that synaptojanin 2 contributes to the role of Rac1 in cell invasion and migration by regulating the formation of invadopodia and lamellipodia. This study also identifies synaptojanin 2 as a novel potential target for therapeutic intervention in malignant tumors.
Highlights
Roles for the Rho family members Rac, Cdc42, and Rho in cell transformation, tumor cell invasion, and metastasis [12,13,14,15]
To examine the role of synaptojanin 2 in glioma cell invasion, we inhibited the expression of synaptojanin 2 using transient transfection of small interfering RNA oligonucleotide duplexes in two different glioblastoma grade IV lines, SNB19 and U87MG
To examine whether the roles of Rac1 and synaptojanin 2 in glioma cell invasion extend to conditions that more closely resemble the in vivo situation, we determined whether RNA interference-mediated depletion of Rac1 or synaptojanin 2 inhibits the invasion of GFPexpressing human glioma cells into rat brain slices, a well-established organotypic model for glioma invasion [30, 31] that we have modified recently [26]
Summary
Show that RNA interference-mediated depletion of synaptojanin 2 strongly inhibits glioma cell invasion and migration. Synaptojanins are a family of phosphatidylinositol (PI) phosphatases that contain two distinct phosphatase domains that are arranged in tandem, a SacI homology domain that acts on PI-3-P, PI-4-P, and PI-3,5-P2 and an inositol 5Ј-phosphatase domain, acting both on PI-4,5-P2 and PI-3,4,5-P3 [1]. There are two synaptojanins in the human genome. The major splice isoform of synaptojanin 1 is brain that depletion of either Rac or synaptojanin 2 inhibits the formation of invadopodia and lamellipodia. These results suggest that synaptojanin 2 mediates Rac1-regulated cell invasion and migration by regulating invadopodia and lamellipodia formation
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