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The Elusive Physiologic Role of Factor XII Alvin H commentaries ar factor-kappaB blockade in multiple myeloma: leads to MAPK pathway activation through a PI3K- 2007. Role of autophagy in cancer. Nat. Rev. Cancer. therapeutic applications. Blood. 99:4079–4086. dependent feedback loop in human cancer. J. Clin. 7:961–967. 12. Kinkade, C.W., et al. 2008. Targeting AKT/mTOR Invest. 118:3065–3074. 18. Kaarbo, M., Klokk, T.I., and Saatcioglu, F. 2007. and ERK MAPK signaling inhibits hormone-refrac- 15. She, Q.B., et al. 2005. The BAD protein integrates Androgen signaling and its interactions with other tory prostate cancer in a preclinical mouse model. survival signaling by EGFR/MAPK and PI3K/Akt signaling pathways in prostate cancer. Bioessays. J. Clin. Invest. 118:3051–3064. kinase pathways in PTEN-deficient tumor cells. 29:1227–1238. 13. Ley, R., et al. 2004. Extracellular signal-regulated Cancer Cell. 8:287–297. 19. Shen, M.M., and Abate-Shen, C. 2007. Pten inac- kinases 1/2 are serum-stimulated “Bim(EL) kinas- 16. Qi, X.J., Wildey, G.M., and Howe, P.H. 2006. Evi- tivation and the emergence of androgen-indepen- es” that bind to the BH3-only protein Bim(EL) dence that Ser87 of BimEL is phosphorylated by dent prostate cancer. Cancer Res. 67:6535–6538. causing its phosphorylation and turnover. J. Biol. Akt and regulates BimEL apoptotic function. 20. Datta, S.R., Brunet, A., and Greenberg, M.E. 1999. Chem. 279:8837–8847. J. Biol. Chem. 281:813–823. Cellular survival: a play in three Akts. Genes Dev. 14. Carracedo, A., et al. 2008. Inhibition of mTORC1 17. Mathew, R., Karantza-Wadsworth, V., and White, E. 13:2905–2927. The elusive physiologic role of Factor XII Alvin H. Schmaier Division of Hematology and Oncology, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio, USA. Physiologic hemostasis upon injury involves many plasma proteins in a can reciprocally activate more FXII and well-regulated cascade of proteolytic reactions to form a clot. Deficiency of liberate bradykinin from high-molecular- blood coagulation Factors VIII, IX, or XI is associated with hemophilia. Fac- weight kininogen (HK). Bradykinin is a tor XII (FXII) autoactivates by contact with a variety of artificial or biologic mediator of vasodilatation and increased negatively charged surfaces (contact activation), resulting in blood coagula- vascular permeability (4). α-FXIIa when tion and activation of the inflammatory kallikrein-kinin and complement cleaved by plasma kallikrein forms Factor systems. However, surprisingly, individuals deficient in FXII rarely suffer βXIIa (β-FXIIa), which then activates the from bleeding disorders. Most biologic surfaces that activate FXII become macromolecular complex of the first com- expressed in disease states. Investigators have long searched for physiologic ponent of complement, resulting in clas- activators of FXII and its role in vivo. In this issue of the JCI, Maas et al. show sic complement system activation; plasma that misfolded protein aggregates produced during systemic amyloidosis kallikrein also directly activates comple- allow for plasma FXIIa and prekallikrein activation and increased forma- ment components C3 and C5 (5, 6). Thus, tion of kallikrein–C1 inhibitor complexes, without Factor XIa activation the activation of FXII results in coagula- and coagulation (see the related article beginning on page 3208). This study tion and complement activation with bra- describes a novel biologic surface for FXII activation and activity, which ini- dykinin liberation (Figure 1). tiates inflammatory events independent of hemostasis. Contact activation of Factor XII In the early 1950s, Oscar Ratnoff and Joan FXI that, when activated to become FXIa, Since FXII-deficient patients, along with Colopy observed a patient, John Hageman, leads to the formation of Factor IXa — a PK- and HK-deficient patients, do not whose blood, upon routine preoperative key intermediary in the intrinsic pathway have a bleeding disorder, the relevance of screening, was found to have prolonged of coagulation. These seminal studies the waterfall cascade hypothesis for blood clotting times in glass test tubes, even contributed to the presentation of their coagulation hemostasis initiated by acti- though Hageman had no history or symp- waterfall cascade hypothesis for the blood vated FXII has been questioned. Contact toms of a bleeding disorder (1). The obser- coagulation system; a similar hypothesis activation describes the unique property vation that something was missing in his was proposed that same year by Robert of FXII to undergo autoactivation and a blood, and that this factor changed upon MacFarlane (2, 3). Ratnoff and his collab- change in shape when exposed to negative- exposure to glass, ushered in the notion orators went on to show that FXII, which ly charged artificial or biologic surfaces. that blood clotting factors circulate as alters its physical properties during activa- Formation of FXIIa leads to PK activation inactive precursors that can be activated. tion, induces vasodilatation and vascular in the presence of HK, hence the name con- Ratnoff, in collaboration with Earl Davie, permeability. These studies encapsulate tact activation system. However, the molecu- identified that, in the disorder that became the major known properties of FXII (Fig- lar basis for the formation of activated known as Hageman trait, a plasma serine ure 1), a protein that autoactivates upon FXII remains unknown (7, 8). Over the last protease later called Factor XII (FXII) was exposure to negatively charged surfaces to 4 decades, a growing list of “physiologic” missing. Absence of FXII prevents the acti- become the enzyme Factor XIIa (α-FXIIa), negatively charged surfaces upon which vation of the blood coagulation zymogen which then activates FXI, prekallikrein FXII autoactivates have been recognized. (PK), and C1 esterase (a subunit of the In addition to nonphysiologic agents such Nonstandard abbreviations used: FXII, Factor XII; complement cascade). The consequence as glass, polyethylene, and silicone rubber, FXIIa, activated FXII; HK, high-molecular-weight of FXI activation by α-FXIIa is the ini- FXII autoactivation occurs upon expo- kininogen; PK, prekallikrein. tiation of a series of proteolytic reactions sure to articular cartilage, skin, fatty acids, Conflict of interest: The author has declared that no conflict of interest exists. resulting in thrombin generation, which endotoxin, amyloid protein, and heparins, Citation for this article: J. Clin. Invest. 118:3006–3009 precedes clot formation. α-FXIIa activa- among others (9). It is in this context of (2008). doi:10.1172/JCI36617. tion of PK forms plasma kallikrein that identifying a biologic surface that sup- 3006 The Journal of Clinical Investigation http://www.jci.org Volume 118 Number 9 September 2008 commentaries deposition of misfolded amyloid proteins in organs and/or tissues, the authors observed significantly elevated levels of activated FXII compared with controls, as assessed by one commercially available assay (10). The authors go on to show that contact activation initiated by FXII in reaction to these misfolded proteins is associated with elevated levels of plasma kallikrein–C1 inhibitor complexes, but not FXIa–C1 inhibitor complexes, both in vitro and in patients with systemic amy- loidosis (10). This latter finding suggests that PK activation (and consequent activa- tion of the inflammatory kallikrein-kinin and complement systems) triggered by FXII autoactivation in reaction to mis- folded or amorphous protein aggregates Figure 1 can proceed independently of the intrinsic Mechanisms for FXII activation. There are two pathways for FXII (Hageman factor) activation: coagulation pathway (Figure 1). autoactivation upon exposure to negatively charged surfaces and proteolytic activation on cell Do the results of the Maas et al. (10) membranes. FXII autoactivates (K = 2.4 M) on an artificial or biologic surface such as kaolin m μ study reveal a major new pathway for FXII or a thrombus to activate FXII to α-FXIIa. α-FXIIa then activates FXI to FXIa to initiate hemo- stasis and activates PK to form plasma kallikrein (KAL). KAL cleaves HK to liberate bradykinin, autoactivation and provide insight regard- which induces vasodilatation and vascular permeability. KAL also activates the complement ing a physiologic activity for FXII? What is system by directly activating complement components C3 and C5 and cleaving α-FXIIa to form intriguing about the current investigation β-FXIIa (a soluble light chain enzymatic form [Hageman factor fragment]), which then activates is that it demonstrates constitutive FXII the macromolecular C1qr,s complex to enzymatically active C1r and C1s. The results of the contact activation in the disease state of study by Maas et al. in this issue of the JCI (10) suggest that a second FXII autoactivation systemic amyloidosis. The data also sug- mechanism occurs upon exposure of FXII to aggregates of misfolded proteins and that this gest that FXII autoactivation in reaction to activation results in PK activation without FXI activation — showing that the kallikrein-kinin misfolded protein initiates an inflamma- system can be activated separately from the coagulation cascade by FXII. A second pathway for FXII activation occurs on endothelial cells. PK bound to HK on endothelial cells is activated tory response in reaction to these abnor- to plasma KAL by the serine protease prolylcarboxypeptidase (PRCP) (Km = 9 nM). KAL then mal protein deposits. Activation of the activates FXII to α-FXIIa
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