CRIF1 deficiency suppresses endothelial cell migration via upregulation of RhoGDI2

PLoS One. 2021 Aug 26;16(8):e0256646. doi: 10.1371/journal.pone.0256646. eCollection 2021.

Abstract

Rho GDP-dissociation inhibitor (RhoGDI), a downregulator of Rho family GTPases, prevents nucleotide exchange and membrane association. It is responsible for the activation of Rho GTPases, which regulate a variety of cellular processes, such as migration. Although RhoGDI2 has been identified as a tumor suppressor gene involved in cellular migration and invasion, little is known about its role in vascular endothelial cell (EC) migration. CR6-interacting factor 1 (CRIF1) is a CR6/GADD45-interacting protein with important mitochondrial functions and regulation of cell growth. We examined the expression of RhoGDI2 in CRIF1-deficient human umbilical vein endothelial cells (HUVECs) and its role in cell migration. Expression of RhoGDI2 was found to be considerably higher in CRIF1-deficient HUVECs along with suppression of cell migration. Moreover, the phosphorylation levels of Akt and CREB were decreased in CRIF1-silenced cells. The Akt-CREB signaling pathway was implicated in the changes in endothelial cell migration caused by CRIF1 downregulation. In addition to RhoGDI2, we identified another factor that promotes migration and invasion of ECs. Adrenomedullin2 (ADM2) is an autocrine/paracrine factor that regulates vascular tone and other vascular functions. Endogenous ADM2 levels were elevated in CRIF1-silenced HUVECs with no effect on cell migration. However, siRNA-mediated depletion of RhoGDI2 or exogenous ADM2 administration significantly restored cell migration via the Akt-CREB signaling pathway. In conclusion, RhoGDI2 and ADM2 play important roles in the migration of CRIF1-deficient endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / deficiency
  • Cell Cycle Proteins / genetics*
  • Cell Movement / genetics
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Endothelial Cells / cytology*
  • Endothelial Cells / metabolism
  • Gene Expression Regulation / genetics
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Peptide Hormones / genetics*
  • Protein Interaction Maps
  • Proto-Oncogene Proteins c-akt / genetics
  • rho Guanine Nucleotide Dissociation Inhibitor beta / genetics*
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors / genetics

Substances

  • ADM2 protein, human
  • ARHGDIB protein, human
  • Cell Cycle Proteins
  • Cyclic AMP Response Element-Binding Protein
  • GADD45GIP1 protein, human
  • Peptide Hormones
  • rho Guanine Nucleotide Dissociation Inhibitor beta
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors
  • Proto-Oncogene Proteins c-akt

Grants and funding

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant number: NRF-2014R1A6A1029617 to BHJ and Grant number: NRF-2019R1I1A3A0105949712 to CSK) and by the research fund of the Chungnam National University to CSK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.