Theme Issue Article Factor XII: New life for an old protein Alvin H. Schmaier; Gretchen LaRusch Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, Ohio, USA Summary 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 acti- vator 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. Pep- tides from uPAR domain 2 block XII binding and ERK1/2 and Akt phos- phorylation. Furthermore, antibodies to the integrins β1 and α5 block XII signalling. Likewise, inhibitors to the EGFR block XII-induced phos- Correspondence to: Dr. Alvin H. Schmaier Case Western Reserve University 10900 Euclid Avenue, WRB2–130 Cleveland, OH 44106–7284, USA Tel.: +1 216 368 1172, Fax: +1 216 368 3014 E-mail: Schmaier@case.edu phorylation events. XII stimulates cell growth and proliferation. XII in- duces angiogenesis ex vivo in normal aortic sprouts and in vivo in ma- trigel plugs in normal mice, but not in aorta from uPAR knockout mice or matrigel plugs placed into uPAR-deleted mice. Skin biopsies consti- tutively 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. Keywords Angiogenesis and inhibitors, contact phase, urokinase / receptor, factor XII, integrins Received: March 10, 2010 Accepted after minor revision: April 12, 2010 Prepublished online: August 30, 2010 doi:10.1160/TH10-03-0171 Thromb Haemost 2010; 104: 915–918 915 © Schattauer 2010 Thrombosis and Haemostasis 104.5/2010 Introduction It was a great privilege to be at this symposium honouring the con- tributions of Oscar Ratnoff. He was the archetype physician-scien- tist triple threat. Although I did not have the opportunity to work with Dr. Ratnoff directly, I grew up in the competing laboratory of Dr. Robert Colman and in the medical community of Sol Sherry – two men who had many interactions with Ratnoff. Suffice-it-to- say, Dr. Ratnoff had much influence on my work. I met him at my first poster presentation at the American Federation of Clinical Re- search meeting in May, 1980 at the Sheraton in Washington, DC. Dr. Ratnoff was a critical reviewer of my first poster on the identi- fication of platelet high-molecular-weight kininogen (1). He must have reviewed my first 18 papers because one reviewer always came back referring to Ratnoff papers published in the Journal of Lab- oratory Clinical Medicine and gently pointing out that my observa- tions in the paper under review were reported by Ratnoff in some publication 10–20 years before. These reviews usually came with the subtle suggestion to review these citations because their con- tents may improve the quality of my work. Finally, Oscar told me an aphorism about researchers which I will never forget. He said that there are two kinds of investigators, one which always looks first at the citations of a new paper in his field to determine how often he is cited and another who does the same thing but will never admit it. Factor XII The recognition of Hageman trait and the discovery that Hageman trait is due to factor FXII (FXII) deficiency is the first of many great contributions to the field of haemostasis and thrombosis by Oscar D. Ratnoff (2, 3). The discovery of FXII allowed for the first hy- pothesis of the mechanism of the blood coagulation to be pro- posed (4, 5). Interest fell in the role of the FXII in physiologic hae- mostasis when one is reminded that FXII-deficient patients have no obvious disease and a physiologic activator for it became elusive (6–8). We sought an alternative to initiation of coagulation acti- vation by FXII autoactivation by recognising that prolylcarboxy- peptidase activates prekallikrein and its formed plasma kallikrein leads to kinetically favourable FXII activation (9,10). Recent other investigations have created new interest in FXII. The FXII-defi- cient mouse was observed to have delayed times to thrombosis, suggesting that FXII participates in thrombosis risk and not in hae- mostasis (11, 12). Furthermore, the presence of FXII contributes to thrombin formation at sites of vessel injury by allowing it to auto- activate on exposed tissue RNA, polysomes from activated pla- telets, aggregated and misfolded protein, or collagen exposed on injured endothelium (13–16). This role of FXII requires its autoac- tivation to FXIIa and serves as an in vivo pathophysiologic activity after vessel damage arising from injury or disease states (Fig. 1). Autoactivation of FXII in vivo may be one of our defense reactions to injury (vessel disruption) and infection (bacterial surfaces) in Ratnoff Symposium 2009 For personal or educational use only. No other uses without permission. All rights reserved. Downloaded from www.thrombosis-online.com on 2017-06-19 | IP: 54.191.40.80