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- W2980208587 abstract "Abstract We have shown that HKa inhibits angiogenesis by inducing detachment and apoptosis of human umbilical vein endothelial cells (HUVECs) from specific extracellular matrix proteins, such as vitronectin and fibrinogen, but not collagen. To investigate which intracellular signaling pathway led to cell detachment, several specific inhibitors were selected and utilized. SP600125, a JNK inhibitor, and PP2, a Src kinase inhibitor, both produced HUVECs detachment from surfaces coated with fibrinogen while MG-132, a NF-κB inhibitor, induced apoptosis. Neither U0126, an ERK inhibitor, nor SB202190, a p38 inhibitor, detached HUVECs from fibrinogen surfaces. By Western blot analysis, we found that HKa inhibited JNK, but not Src kinase activity. Previous investigators have demonstrated Rho-associated protein kinase (ROCK) regulates the JNK pathway. We demonstrated that Y27632, a ROCK inhibitor, not only inhibited JNK activity, but also caused detachment of HUVECs. Using phospho-antibodies, we found that HKa decreased the phosphorylation of paxillin at Ser178 site, but not Tyr 118 site indicating a serine kinase. Paxillin is a multi-domain adaptor found at the interface between the plasma membrane and the actin cytoskeleton. Paxillin phosphorylation is known to be associated with the coordinate formation of focal adhesions and stress fibres. Since the Ser178 of paxillin is a substrate for JNK, while Tyr 118 is a substrate for FAK and Src, it appears that JNK is responsible. Our studies have uncovered the novel finding that HKa detached HUVECs from fibrinogen through the ROCK-JNK-paxillin (Ser178) pathway, but not Src-paxillin (Tyr118) signaling." @default.
- W2980208587 created "2019-10-18" @default.
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- W2980208587 date "2006-11-16" @default.
- W2980208587 modified "2023-09-29" @default.
- W2980208587 title "Detachment of Human Endothelial Cells from Fibrinogen Induced by Cleaved High Molecular Weight Kininogen (HKa) Is Mediated by c-Jun Amino-Terminal Kinase (JNK) Signaling Pathway." @default.
- W2980208587 doi "https://doi.org/10.1182/blood.v108.11.1809.1809" @default.
- W2980208587 hasPublicationYear "2006" @default.
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