Factor XII-induced mitogenesis is mediated via a distinct signal transduction pathway that activates a mitogen-activated protein kinase.

Abstract

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 XIIinduced 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 XlI-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 signalregulated 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.

The structure of the FnI-EGF-like tandem domain of coagulation factor XII solved using SIRAS

“…The putative interaction of FXII with the EGF receptor has been implicated in stimulating the division of cells (Schmeidler-Sapiro et al, 1991;Gordon et al, 1996) with EGF and TGFa (Garrett et al, 2002;Ogiso et al, 2002) served as templates to dock FXII-FnIE to EGFR. A superposition of the FXIIFnIE structure onto that of EGF bound to EGFR showed that the FnI domain overlaps with domain I of EGFR (Fig.…”

“…Extensive research has been performed on the type of surfaces and molecules that activate FXII in vitro, leading to initiation of the intrinsic coagulation pathway and the kallikreinkinin system (Griep et al, 1986;Tazi et al, 1992;Matata et al, 1996). The search for a physiological function of FXII has resulted in a number of possible roles, such as the induction of mitosis (Schmeidler-Sapiro et al, 1991;Gordon et al, 1996), angiogenesis (LaRusch et al, 2010), inflammation reactions (Jansen et al, 1996) and complement activation (Ghebrehiwet et al, 1981). Additionally, FXII has been found to have an important role in thrombus formation (Renné et al, 2005;Meijden et al, 2009).…”

“…The binding of FXII to the surface of these cells results in the activation of several kinase signalling pathways, leading to mitosis. Some studies have attributed this to interaction between one of the EGF-like domains of FXII and the EGF receptor (EGFR) on these cells (Schmeidler-Sapiro et al, 1991;Gordon et al, 1996). An indirect activation model has also been proposed in which FXII binds to the uPA receptor via its FnII domain, after which a multiple receptor complex is formed (LaRusch et al, 2010).…”

The elusive physiologic role of Factor XII

“…FXII binding to endothelial membranes is highly regulated by the plasma concentration of HK and Zn 2+ (21). FXII, when bound to cells, stimulates ERK1/2 phosphorylation and [ 3 H]thymidine uptake (22) (Figure 1).…”

Heparan Sulfate Proteoglycans Mediate Factor XIIa Binding to the Cell Surface

“…Moreover, our unpublished results 4 demonstrating potent mitogenic activities of FXIIa toward HLF further support a role of FXIIa in fibrogenesis. The ability of FXII/FXIIa to stimulate proliferation of alveolar type II cells, aortic smooth muscle cells, hepatocytes, and endothelial cells has been described previously (43,44). Furthermore, FXII/FXIIa-induced endothelial cell proliferation was shown to be physiologically relevant because it had a profound impact on angiogenesis (45).…”