A Truncated Kringle Domain of Human Apolipoprotein(a) Inhibits the Activation of Extracellular Signal-regulated Kinase 1 and 2 through a Tyrosine Phosphatase-dependent Pathway

• Published in: The Journal of biological chemistry Vol. 279; no. 21; pp. 21808 - 21814
• Main Authors: Ahn, Jin-Hyung, Kim, Jang-Seong, Yu, Hyun-Kyung, Lee, Ho-Jeong, Yoon, Yeup
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 21.05.2004
• Subjects: Apolipoproteins A - chemistry; Apolipoproteins A - metabolism; Blotting, Western; Cell Movement; Cells, Cultured; Dose-Response Relationship, Drug; Endothelium - pathology; Endothelium, Vascular - cytology; Enzyme Activation; Humans; Kringles; Microscopy, Fluorescence; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Neovascularization, Pathologic; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Phosphorylation; Protein Structure, Tertiary; Protein Tyrosine Phosphatases - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Signal Transduction; Umbilical Veins - cytology; Vanadates - pharmacology; Wound Healing
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M313633200

Most proangiogenic factors exert their biological effects primarily by activating extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3-K)/Akt signaling pathways. These pathways appear to play a critical role in endothelial cell migration, because selective inhibition of either ERK or PI3-K/Akt signaling almost completely prevented endothelial cell migration. Recently, we demonstrated that a truncated kringle domain of human apolipoprotein(a), termed rhLK68, inhibits endothelial cell migration in vitro . However, its mechanism of action was not well defined. In this study, we determined the effects of rhLK68 on ERK1/2 and PI3-K/Akt signaling pathways to explore the molecular mechanism of rhLK68-mediated inhibition of endothelial cell migration. Treatment with rhLK68 inhibited ERK1/2 phosphorylation but did not influence Akt activation. Interestingly, an inhibitor of protein-tyrosine phosphatase, sodium orthovanadate, dose-dependently reversed both rhLK68-induced dephosphorylation of ERK1/2 and decreased migration of endothelial cells, whereas rhLK68 showed no significant effects on MEKs phosphorylation. In conclusion, these results indicate that inhibition of endothelial cell migration by rhLK68 may be achieved by interfering with ERK1/2 activation via a protein-tyrosine phosphatase-dependent pathway.