| text | Binding of factor XII (FXII) to cell surface receptors facilitates the assembly of high molecular weight kininogen (HK), prekallikrein (PK), and FXII into higher order ternary complexes, in which FXIIa and plasma kallikrein (PKa) mutually activate each other in a Zn²⁺-dependent manner, creating a positive feedback loop on the cell surface (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). This Reactome event describes plasma kallikrein-catalyzed cleavage of FXII within the cell surface receptor complexes, leading to the release of activated FXIIa. The cell surface receptors involved in this process include complement C1q binding protein, encoded by the C1QBP gene, also known as globular C1q receptor (gC1qR), cytokeratin 1 (CK1, encoded by the KRT1 gene), and the urokinase plasminogen activator receptor (uPAR, encoded by the PLAUR gene). Both gC1qR (C1QBP) and uPAR (PLAUR) interact with CK1, forming heterodimers gC1qR:CK1 and uPAR:CK1 complexes, respectively. Additionally, gC1qR (C1QBP) may function as a homotrimer (Ghebrehiwet B et al., 1994; 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). Although gC1qR, CK1 and uPAR are expressed on various cell types, including activated platelets (Peerschke EIB et al., 2003; Khan MM et al., 2006; reviewed by Schmaier AH, 2016), FXII induced activation of the plasma kallikrein kinin system is thought to occur predominantly on endothelial cell surfaces (Lin Y et al., 1997; Motta G et al., 1998; Joseph K et al., 2001; Mahdi F et al., 2002, 2003; Pixley RA et al., 2011; Kaira BG et al., 2020). |
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