FACTOR XII-INDUCED MITOGENESIS IS MEDIATED VIA A DISTINCT SIGNAL-TRANSDUCTION PATHWAY THAT ACTIVATES A MITOGEN-ACTIVATED PROTEIN-KINASE

Clotting factor XII (Hageman factor) contains epidermal growth factor (EGF)-homologous domains and is reported to be a potent mitogen for hu man hepatoma (HepG2) cells, In this study, we tested whether factor XI I exhibits growth factor activity on several other EGF-sensitive targe t cells, including fetal hepatocytes, endothelial cells, alveolar type II cells, and aortic smooth muscle cells, We found that factor XII si gnificantly enhanced [H-3]thymidine incorporation in aortic smooth mus cle cells (SMCs) and all other cells tested, Tyrphostin, a growth fact or receptor/tyrosine kinase antagonist, inhibited both EGF- and factor XII-induced responses, However, differences in the levels of magnitud e of DNA synthesis, the observed synergism between EGF and factor XII, and the differential sensitivity to tyrphostin suggest that the EGF r eceptor and the factor XII receptor may be nonidentical, The factor XI I-induced mitogenic response was achieved at concentrations that were 1/10th the physiologic range for the circulating factor and was reduce d by popcorn inhibitor, a specific factor XII protease inhibitor, Trea tment of aortic SMCs with factor XII, as well as activated factor XII, resulted in a rapid and transient activation of a mitogen-activated/e xtracellular signal-regulated protein kinase,vith peak activity/tyrosi ne phosphorylation observed at 5 to 10 min of exposure, Taken together , these data (i) confirm that clotting factor XII functions as a mitog enic growth factor and (ii) demonstrate that factor XII activates a si gnal transduction pathway, which includes a mitogen-activated protein kinase.