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.