Factor XII: New life for an old protein
10 March 2010
Accepted after minor revision: 12 April 2010
24 November 2017 (online)
Ratnoff and his coworkers recognised that factor XII (XII) stimulates cell growth and activates mitogen-activated protein kinase. We determined the receptor(s) for this function and the consequence of this signalling pathway. Investigations show that the urokinase plasminogen activator receptor serves as the XII binding site on cultured umbilical vein endothelial cells. When XII binds, it stimulates ERK1/2 and Akt S473 phosphorylation. These events are distinct because when cell mTORC2 is absent, XII phosphorylates ERK1/2 but not Akt S473. Zymogen XII is an equal stimulator of signalling as XIIa or inhibitor-treated XIIa. Peptides from uPAR domain 2 block XII binding and ERK1/2 and Akt phosphorylation. Furthermore, antibodies to the integrins β1 and α5 block XII signalling. Likewise, inhibitors to the EGFR block XII-induced phosphorylation events. XII stimulates cell growth and proliferation. XII induces angiogenesis ex vivo in normal aortic sprouts and in vivo in matrigel plugs in normal mice, but not in aorta from uPAR knockout mice or matrigel plugs placed into uPAR-deleted mice. Skin biopsies constitutively or in a wound nine days after injury show reduced CD31 antigen expression in specimens from XII knockout mice compared to wild-type mice. These studies indicate that XII stimulates angiogenesis, a physiologic function independent of contact activation.
- 1 Schmaier AH. et al. High molecular weight kininogen: A secreted platelet protein. J Clin Invest 1983; 71: 1477-1489.
- 2 Ratnoff OD, Colopy JE. A familial hemorrhagic trait associated with a deficiency of clot formation fraction of plasma. J Clin Invest 1955; 34: 602-613.
- 3 Ratnoff OD. et al. Studies on the action of Hageman factor: evidence that activated Hageman factor in turn activates plasma thromboplastin antecedent. J Clin Invest 1961; 40: 803-819.
- 4 Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood coagulation. Science 1964; 145: 1310-1320.
- 5 Macfarlane RG. An enzyme cascade in the blood clotting mechanism, and its functions as a biochemical amplifier. Nature 1964; 202: 498-499.
- 6 Wilner GD. et al. Activation of Hageman factor by collagen. J Clin Invest 1968; 47: 2608-2615.
- 7 Ratnoff OD. Activation of Hageman factor by L-homocystine. Science 1968; 162: 1007-1009.
- 8 Zacharski LR, Rosenstein R. Failure of collagen to activate factor XII. Thromb Res 1975; 07: 929-933.
- 9 Shariat-Madar Z. et al. Identifcation and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J Biol Chem 2002; 277: 17962-17969.
- 10 Rojkjaer R. et al. Factor XII does not initiate prekallikrein activation on endothelial cells. Thromb Haemost 1998; 80: 74-81.
- 11 Renne T. et al. Defective thrombus formation in mice lacking coagulation factor XII. J Exp Med 2005; 202: 271-281.
- 12 Kleinschnitz C. et al. Targeting coagulation factor XII provides protection from pathologic thrombosis in cerebral ischemia without interfering with hemostasis. J Exp Med 2006; 203: 513-518.
- 13 Kannemeier C. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 2007; 104: 6388-6393.
- 14 Smith SA. et al. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci USA 2006; 103: 903-908.
- 15 Maas C. et al. Misfolded proteins activate factor XII in humans, leading to kallik-rein formation without initiating coagulation. J Clin Invest 2008; 118: 3208-3218.
- 16 van der Meijden PEJ. et al. Dual role of collagen in factor XII-dependent thrombus formation. Blood 2009; 114: 881-890.
- 17 Stavrou E, Schmaier AH. Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis and thrombosis. Thromb Res 2010; 125: 210-215.
- 18 Citarella F. et al. Identification of a putative binding site for negatively charged surfaces in the fibronectin type II domain of human factor XII-an immuno-chemical and homology modeling approach. Thromb Haemost 2000; 84: 1057-1065.
- 19 Mahdi F. et al. Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes. Blood 2002; 99: 3585-3596.
- 20 Mahdi F. et al. Expression and colocalization of cytokeratin 1 and urokinase plasminogen activator receptor on endothelial cells. Blood 2001; 97: 2342-2350.
- 21 Mahdi F. et al. Mapping the interaction between high molecular weight kininogen and the urokinase plasminogen activator receptor. J Biol Chem 2004; 279: 16621-16628.
- 22 Li Y. et al. Sequences within domain II of the urokinase receptor critical for differential ligand recognition. J Biol Chem 2003; 278: 29925-29932.
- 23 LaRusch GA. et al. Factor XII stimulates ERK1/2 and Akt through uPAR, inte-grins, and the EGFR ti initiate angiogenesis. Blood 2010; 115: 5111-5120.
- 24 Chien P. et al. Modulation of the human monocyte binding site for monomeric immunoglobulin G by activated Hageman factor. J Clin Invest 1988; 82: 1554-1559.
- 25 Cool DE, MacGillivray RT. Characterization of the human blood coagulation factor XII gene. Intron/exon gene organization and analysis of the 5’-flanking region. J Biol Chem 1987; 262: 13662-13672.
- 26 Schmeidler-Sapiro KT. et al. Mitogenic effects of coagulation factor XII and factor XIIa on HepG2 cells. Proc Natl Acad Sci USA 1991; 88: 4382-4385.
- 27 Gordon EM. et al. Factor XII-induced mitogenesis is mediated via a distinct signal transduction pathway that activates a mitogen-activated protein kinase. Proc Natl Acad Sci USA 1996; 93: 2174-2179.
- 28 Fernando AN. et al. Assembly, activation, and signaling by kinin-forming on human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 2005; 289: H251-H257.
- 29 Jacinto E. et al. SIN1/MIP1 maintains rector-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 2006; 127: 125-137.
- 30 Wei Y. et al. Regulation of alpha5beta1 integrin conformation and function by urokinase receptor binding. J Cell Biol 2005; 168: 501-511.
- 31 Jo M. et al. Epidermal growth factor receptor-dependent and-independent cell-signaling pathways originating from the urokinase receptor. J Biol Chem 2003; 278: 1642-1646.
- 32 Blacher S. et al. Improved quantification of angiogenesis in the aortic ring assay. Angiogenesis 2001; 04: 133-142.
- 33 Schmaier AA, Schmaier AH. Thrombosis in flowing blood. Blood 2009; 114: 754-756.