Mechanisms for vascular cell adhesion molecule-1 activation of ERK1/2 during leukocyte transendothelial migration

• Published in: PloS one 2011-10, Vol.6 (10), p.e26706-e26706
• Main Authors: Abdala-Valencia, Hiam, Berdnikovs, Sergejs, Cook-Mills, Joan M
• Format: Article
• Language: English
• Subjects: Adhesion; Animals; Biology; Blotting, Western; Butadienes - pharmacology; Cell activation; Cell adhesion; Cell adhesion & migration; Cell adhesion molecules; Cell Line; Cytokines; Electrophoresis, Polyacrylamide Gel; Endothelial cells; Endothelium; Enzyme Inhibitors - pharmacology; Extracellular signal-regulated kinase; Flavonoids - pharmacology; Humans; Immunoglobulins; Immunology; Inflammation; Inhibitors; Kinases; Laminar flow; Leukocyte migration; Leukocytes; Leukocytes - cytology; Ligands; Lymphatic system; Lymphocytes; Medicine; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; NAD(P)H oxidase; NADPH Oxidases - metabolism; Nitriles - pharmacology; Oxidase; Oxidases; Pharmacology; Phosphatase; Phosphatases; Phosphorylation; Physiological aspects; Protein kinase; Protein kinase C; Protein Kinase C-alpha - metabolism; Protein kinases; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Protein-tyrosine-phosphatase; Proteins; Rats; Rheology; Rodents; Signal transduction; Signal Transduction - drug effects; Signaling; Tissues; Transendothelial and Transepithelial Migration - drug effects; Transendothelial and Transepithelial Migration - physiology; Tyrosine; Vascular cell adhesion molecule 1; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0026706

During inflammation, adhesion molecules regulate recruitment of leukocytes to inflamed tissues. It is reported that vascular cell adhesion molecule-1 (VCAM-1) activates extracellular regulated kinases 1 and 2 (ERK1/2), but the mechanism for this activation is not known. Pharmacological inhibitors of ERK1/2 partially inhibit leukocyte transendothelial migration in a multi-receptor system but it is not known whether VCAM-1 activation of ERK1/2 is required for leukocyte transendothelial migration (TEM) on VCAM-1. In this study, we identified a mechanism for VCAM-1 activation of ERK1/2 in human and mouse endothelial cells. VCAM-1 signaling, which occurs through endothelial cell NADPH oxidase, protein kinase Cα (PKCα), and protein tyrosine phosphatase 1B (PTP1B), activates endothelial cell ERK1/2. Inhibition of these signals blocked VCAM-1 activation of ERK1/2, indicating that ERK1/2 is activated downstream of PTP1B during VCAM-1 signaling. Furthermore, VCAM-1-specific leukocyte migration under physiological laminar flow of 2 dynes/cm(2) was blocked by pretreatment of endothelial cells with dominant-negative ERK2 K52R or the MEK/ERK inhibitors, PD98059 and U0126, indicating for the first time that ERK regulates VCAM-1-dependent leukocyte transendothelial migration. VCAM-1 activation of endothelial cell NADPH oxidase/PKCα/PTP1B induces transient ERK1/2 activation that is necessary for VCAM-1-dependent leukocyte TEM.