Plasminogen kringle 5 induces endothelial cell apoptosis by triggering a voltage-dependent anion channel 1 (VDAC1) positive feedback loop.
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.
['Li|Lei|L|', 'Yao|Ya-Chao|YC|', 'Gu|Xiao-Qiong|XQ|', 'Che|Di|D|', 'Ma|Cai-Qi|CQ|', 'Dai|Zhi-Yu|ZY|', 'Li|Cen|C|', 'Zhou|Ti|T|', 'Cai|Wei-Bin|WB|', 'Yang|Zhong-Han|ZH|', 'Yang|Xia|X|', 'Gao|Guo-Quan|GQ|']
D017209:Apoptosis D015153:Blotting, Western D020169:Caspases D002478:Cells, Cultured D004305:Dose-Response Relationship, Drug D025461:Feedback, Physiological D038362:Glycogen Synthase Kinase 3 D000071679:Glycogen Synthase Kinase 3 beta D057809:HEK293 Cells D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D008928:Mitochondria D010446:Peptide Fragments D010766:Phosphorylation D010958:Plasminogen D011485:Protein Binding D051057:Proto-Oncogene Proteins c-akt D034622:RNA Interference D015398:Signal Transduction D025801:Ubiquitin D050995:Voltage-Dependent Anion Channel 1
Apoptosis Phosphorylation Bax Cell Biology Cell Signaling Cell Surface Receptor Cellular Regulation Glycogen Synthase Kinase 3 (GSK-3) Molecular Cell Biology PI 3-Kinase (PI3K)