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Factor XII-Induced Mitogenesis is Mediated Via a Distinct Signal Transduction Pathway that Activates a Mitogen-Activated Protein Kinase
Erlinda M. Gordon, Natarajan Venkatesan, Roberto Salazar, Hui Tang, Katherine Schmeidler-Sapiro, Susan Buckley, David Warburton and Frederick L. Hall
Proceedings of the National Academy of Sciences of the United States of America
Vol. 93, No. 5 (Mar. 5, 1996), pp. 2174-2179
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/38486
Page Count: 6
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Clotting factor XII (Hageman factor) contains epidermal growth factor (EGF)-homologous domains and is reported to be a potent mitogen for human hepatoma (HepG2) cells. In this study, we tested whether factor XII exhibits growth factor activity on several other EGF-sensitive target cells, including fetal hepatocytes, endothelial cells, alveolar type II cells, and aortic smooth muscle cells. We found that factor XII significantly enhanced [3H]thymidine incorporation in aortic smooth muscle cells (SMCs) and all other cells tested. Tyrphostin, a growth factor receptor / tyrosine kinase antagonist, inhibited both EGF- and factor XII-induced responses. However, differences in the levels of magnitude of DNA synthesis, the observed synergism between EGF and factor XII, and the differential sensitivity to tyrphostin suggest that the EGF receptor and the factor XII receptor may be nonidentical. The factor XII-induced mitogenic response was achieved at concentrations that were 1 / 10th the physiologic range for the circulating factor and was reduced by popcorn inhibitor, a specific factor XII protease inhibitor. Treatment of aortic SMCs with factor XII, as well as activated factor XII, resulted in a rapid and transient activation of a mitogen-activated / extracellular signal-regulated protein kinase with peak activity / tyrosine phosphorylation observed at 5 to 10 min of exposure. Taken together, these data (i) confirm that clotting factor XII functions as a mitogenic growth factor and (ii) demonstrate that factor XII activates a signal transduction pathway, which includes a mitogen-activated protein kinase.
Proceedings of the National Academy of Sciences of the United States of America © 1996 National Academy of Sciences