期刊
CELL CALCIUM
卷 94, 期 -, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ceca.2020.102330
关键词
Zinc signaling; ZnR; GPR39; KCC; Invasion; MMP; Stress fibers
类别
资金
- Israel Science Foundation [891/14, 812/20]
Activation of ZnR/GPR39 by Zn2+ regulates cell volume through K+/Cl- co-transporter KCC3, promoting cell proliferation and migration. Additionally, upregulation of KCC3 by ZnR/GPR39 enhances the activity of matrix metalloproteases MMP2 and MMP9.
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 Zn2+ activation of the Gqcoupled 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 Zn2+ 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.
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