Plasminogen kringle 5 induces endothelial cell apoptosis by triggering a voltage-dependent anion channel 1 (VDAC1) positive feedback loop

J Biol Chem. 2014 Nov 21;289(47):32628-38. doi: 10.1074/jbc.M114.567792. Epub 2014 Oct 8.


Human plasminogen kringle 5 (K5) is known to display its potent anti-angiogenesis effect through inducing endothelial cell (EC) apoptosis, and the voltage-dependent anion channel 1 (VDAC1) has been identified as a receptor of K5. However, the exact role and underlying mechanisms of VDAC1 in K5-induced EC apoptosis remain elusive. In the current study, we showed that K5 increased the protein level of VDAC1, which initiated the mitochondrial apoptosis pathway of ECs. Our findings also showed that K5 inhibited the ubiquitin-dependent degradation of VDAC1 by promoting the phosphorylation of VDAC1, possibly at Ser-12 and Thr-107. The phosphorylated VDAC1 was attenuated by the AKT agonist, glycogen synthase kinase (GSK) 3β inhibitor, and siRNA, suggesting that K5 increased VDAC1 phosphorylation via the AKT-GSK3β pathway. Furthermore, K5 promoted cell surface translocation of VDAC1, and binding between K5 and VDAC1 was observed on the plasma membrane. HKI protein blocked the impact of K5 on the AKT-GSK3β pathway by competitively inhibiting the interaction of K5 and cell surface VDAC1. Moreover, K5-induced EC apoptosis was suppressed by VDAC1 antibody. These data show for the first time that K5-induced EC apoptosis is mediated by the positive feedback loop of "VDAC1-AKT-GSK3β-VDAC1," which may provide new perspectives on the mechanisms of K5-induced apoptosis.

Keywords: Apoptosis; Bax; Cell Biology; Cell Signaling; Cell Surface Receptor; Cellular Regulation; Glycogen Synthase Kinase 3 (GSK-3); Molecular Cell Biology; PI 3-Kinase (PI3K); Phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Blotting, Western
  • Caspases / metabolism
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Feedback, Physiological / drug effects
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Peptide Fragments / genetics
  • Peptide Fragments / pharmacology*
  • Phosphorylation / drug effects
  • Plasminogen / genetics
  • Plasminogen / pharmacology*
  • Protein Binding
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Ubiquitin / metabolism
  • Voltage-Dependent Anion Channel 1 / genetics
  • Voltage-Dependent Anion Channel 1 / metabolism*


  • Peptide Fragments
  • Ubiquitin
  • VDAC1 protein, human
  • plasminogen kringle 5
  • Plasminogen
  • Voltage-Dependent Anion Channel 1
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Caspases