Reactome | prekallikrein:kininogen:cell surface receptor:factor XII -> factor XIIa + prekallikrein:kininogen:cell surface receptor (FXII autocatalysis on the cell surface)

prekallikrein:kininogen:cell surface receptor:factor XII -> factor XIIa + prekallikrein:kininogen:cell surface receptor (FXII autocatalysis on the cell surface)

Stable Identifier

R-HSA-9857814

Type

Reaction [transition]

Species

Homo sapiens

Compartment

extracellular region, plasma membrane

Synonyms

KLKB1:KNG1:(C1QBP,C1QBP:KRT1, PLAUR:KRT1):FXII -> FXIIa + KLKB1:KNG1:(C1QBP, C1QBP:KRT1, PLAUR:KRT1)

ReviewStatus

5/5

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prekallikrein:kininogen:cell surface receptor:factor XII -> factor XIIa + prekallikrein:kininogen:cell surface receptor (FXII autocatalysis on the cell surface)

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Binding of coagulation factor XII (FXII) to cell surface receptors facilitates the assembly of high-molecular-weight kininogen (HK), prekallikrein (PK), and FXII into a higher-order ternary complex - prekallikrein:kininogen:cell surface receptor:FXII (Joseph K et al., 1999, 2001, 2004; Mahdi F et al., 2002, 2003; Kaira BG et al., 2020; reviewed by Pathak M et al., 2018). Autocatalysis of FXII within this complex results in a cleavage of a single peptide bond at R372, converting FXII to its activated form, FXIIa (Samuel M et al., 1992; Ivanov I et al., 2017; Shamanaev A et al., 2022; reviewed by Shamanaev A, Litvak M et al., 2023).

The cell surface receptors involved in this process include complement C1q-binding protein (C1QBP, known as globular C1q receptor or gC1qR), cytokeratin 1 (CK1, encoded by the KRT1 gene), and urokinase plasminogen activator receptor (uPAR, encoded by the PLAUR gene). Both gC1qR (C1QBP) and uPAR (PLAUR) interact with CK1 (KRT1) forming heterodimers gC1qR:CK1 and uPAR:CK1, respectively (Pixley RA et al, 2011). Additionally, gC1qR (C1QBP) may function as a homotrimer (Joseph K et al., 1999, 2001, 2004; Mahdi F et al., 2002, 2003; Kaira BG et al., 2020; reviewed by Pathak M et al., 2018) and a heterotrimer with HK and FXII (Kaira BG et al., 2020). CK1 and gC1qR are expressed on surfaces of various cell types, including endothelial cells and platelets, and are involved in regulating inflammation, clot formation, and cellular adhesion processes (Mahdi F et al., 2002; Peerschke EIB et al., 2003; Pixley RA et al., 2011; Kaira BG et al., 2020). Importantly, uPAR expressed on the surfaces of endothelial cells and neutrophils, as well as in renal tissue, mediates non-canonical signaling functions of zymogen FXII through β1-integrins. These interactions promote endothelial cell growth, proliferation, and neoangiogenesis; regulate neutrophil adhesion, migration, chemotaxis, and NETosis; and, in the kidney, limit diabetes-associated renal fibrosis through induction of cellular senescence (LaRusch GA et al., 2010; Stavrou EX et al., 2018, Elwakiel A et al., 2024, Kalina D et al., 2025).

Upon binding to the cell surface, FXII undergoes a conformational change that exposes its catalytic domain, which remains hidden in the zymogen state due to interactions between the fibronectin type 2 and kringle domains of FXII (reviewed by Shamanaev A, Litvak M et al., 2023). Surface-bound FXII exhibits catalytic activity towards itself and prekallikrein, converting it to kallikrein. Once activated, FXIIa and kallikrein (PKa) reciprocally activate their respective zymogens in a Zn²⁺-dependent manner, creating a positive feedback loop.

Literature References

PubMed ID	Title	Journal	Year
11204562	Factor XII-dependent contact activation on endothelial cells and binding proteins gC1qR and cytokeratin 1 Joseph, K, Shibayama, Y, Ghebrehiwet, B, Kaplan, AP	Thromb Haemost	2001
25039405	Single-chain factor XII exhibits activity when complexed to polyphosphate Engel, R, Brain, CM, Paget, J, Lionikiene, AS, Mutch, NJ	J Thromb Haemost	2014
14691562	The physiologic basis of assembly and activation of the plasma kallikrein/kinin system Schmaier, AH	Thromb Haemost	2004
874082	Activation and function of human Hageman factor. The role of high molecular weight kininogen and prekallikrein. Meier, HL, Pierce, JV, Colman, RW, Kaplan, AP	J Clin Invest	1977
1066663	Mechanisms for the involvement of high molecular weight kininogen in surface-dependent reactions of Hageman factor Griffin, JH, Cochrane, CG	Proc Natl Acad Sci U S A	1976
6604055	Amino acid sequence of human beta-factor XIIa Fujikawa, K, McMullen, BA	J Biol Chem	1983
7391081	Autoactivation of human Hageman factor. Demonstration utilizing a synthetic substrate. Silverberg, M, Dunn, JT, Garen, L, Kaplan, AP	J Biol Chem	1980
11986212	Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes Mahdi, F, Shariat-Madar, Z, Figueroa, CD, Schmaier, AH	Blood	2002
3886654	Amino acid sequence of the heavy chain of human alpha-factor XIIa (activated Hageman factor) McMullen, BA, Fujikawa, K	J Biol Chem	1985