Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Department of Physiology and Cell Biology and The Zlotowski Center for Neuroscience, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Cell Calcium. 2021 Mar;94:102330. doi: 10.1016/j.ceca.2020.102330. Epub 2021 Jan 16.
Actin re-organization and degradation of extracellular matrix by metalloproteases (MMPs) facilitate formation of cellular protrusions that are required for cell proliferation and migration. We find that Zn activation of the Gq-coupled receptor ZnR/GPR39 controls these processes by regulating K/Cl co-transporter KCC3, which modulates cell volume. Silencing of KCC3 expression or activity reverses ZnR/GPR39 enhancement of cell proliferation, migration and invasion through Matrigel. Activation of ZnR/GPR39 recruits KCC3 into F-actin rich membrane protrusions, suggesting that it can locally control volume changes. Immunofluorescence analysis indicates that Zn activation of ZnR/GPR39 and KCC3 are required to enhance formation of F-actin stress fibers and cellular protrusions. In addition, ZnR/GPR39 upregulation of KCC3-dependent transport increases the activity of matrix metalloproteases MMP2 and MMP9. Our study establishes a mechanism in which ZnR/GPR39 orchestrates localization and activation of KCC3, formation of F-actin rich cell protrusions and activation of MMPs, and thereby controls cell proliferation and migration.
肌动蛋白的重新组织和细胞外基质的降解通过金属蛋白酶（MMPs）促进细胞突起的形成，这对于细胞增殖和迁移是必需的。我们发现，Gq 偶联受体 ZnR/GPR39 的锌激活通过调节 K/Cl 共转运蛋白 KCC3 来控制这些过程，KCC3 调节细胞体积。沉默 KCC3 的表达或活性可逆转 ZnR/GPR39 通过基质胶增强细胞增殖、迁移和侵袭的作用。ZnR/GPR39 的激活将 KCC3 募集到富含 F-肌动蛋白的膜突起中，表明它可以局部控制体积变化。免疫荧光分析表明，Zn 激活 ZnR/GPR39 和 KCC3 增强 F-肌动蛋白应力纤维和细胞突起的形成。此外，ZnR/GPR39 上调 KCC3 依赖性转运增加了基质金属蛋白酶 MMP2 和 MMP9 的活性。我们的研究建立了一种机制，其中 ZnR/GPR39 协调 KCC3 的定位和激活、富含 F-肌动蛋白的细胞突起的形成以及 MMP 的激活，从而控制细胞增殖和迁移。
