| text | Surface-bound prekallikrein (PK), encoded by the KLKB1 gene (depicted here as KLKB1(20–638)), is cleaved to kallikrein, a heterodimer consisting of a light chain (KLKB1(391–638)) and a heavy chain (KLKB1(20–390)). This reaction is catalyzed by the prolylcarboxypeptidase (PRCP) dimer on the cell surface independent of factor XII-driven contact activation (Moreira CR et a., 2002; Shariat-Madar Z et al., 2002, 2004; Wang J et al., 2014; Merkulova AA et al., 2023; reviewed by Schmaier AH et al., 2016). In plasma, prekallikrein (KLKB1(20–638)) specifically associates with high-molecular-weight kininogen (HK, encoded by the KNG1 gene), which binds to cell surface receptors forming the prekallikrein:kininogen:cell surface receptor complex (Shariat-Madar Z et al., 2002; reviewed by Renné T et al., 2012; Pathak M et al., 2018). In vivo, this reaction is thought to occur primarily on the surfaces of endothelial cells in response to platelet activation (Lin Y et al., 1997; Motta G et al., 1998; Joseph K et al., 2004; Pixley RA et al., 2011). The endothelial cell membrane-bound PRCP proteolytically cleaves prekallikrein on the cell surface (Moreira CR et a., 2002; Shariat-Madar Z et al., 2002; Merkulova AA et al., 2023). Additionally, activated factor XIIa (FXIIa) contributes to kallikrein formation both in vitro and in vivo (Revak SD et al., 1978; Iwaki T & Castellino FJ, 2006; reviewed by Renné T et al., 2012). The serine protease activity of PRCP facilitates kinetically favorable prekallikrein activation (Km = 9 nM) compared to FXIIa-mediated activation (Km = 2.4 μM) on negatively charged surfaces in vitro (Røjkjaer R et al., 1998; Shariat-Madar Z et al., 2002, 2004). Additionally, studies in human umbilical vein endothelial cells (HUVECs) have suggested that heat shock protein 90 (HSP90) may function as a kallikrein activator (Joseph et al., 2002). In these studies, HSP90 was proposed to act as a fluid-phase, rather than membrane-bound, activator of prekallikrein when in complex with high-molecular-weight kininogen (HK) (Joseph K et al., 2002). These findings need independent confirmation. Activated plasma kallikrein may remain bound to the kininogen:cell surface receptor complex (Motta G et al., 1998; Zhao Y et al., 2001), where it subsequently cleaves kininogen, releasing bradykinin, a vasoactive peptide, that promotes inflammation (Cochrane CG et al., 1973; Zhao Y et al., 2001). Additionally, formed plasma kallikrein amplifies the contact activation system by cleaving FXII into its active form, FXIIa, contributing to FXII-induced inflammatory and thrombotic responses (reviewed by Renné T et al., 2012). The cell surface receptors involved in this process include complement C1q-binding protein (C1QBP, also known as globular C1q receptor or 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 (KRT1), forming heterodimers gC1qR:CK1 and uPAR:CK1, respectively. Additionally, gC1qR 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) and a heterotrimer with HK and FXII (Kaira BG et al., 2020).
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