Model of zymogen FXII signaling pathway. FXII binds to domain 2 of uPAR and induces uPAR to communicate intracellularly through β₁ integrins. Monoclonal antibody 6S6 to β₁ integrin blocks this pathway. Cell stimulation through uPAR and integrin requires an interaction with 1 or more of the ErbB receptor kinases because the tyrosine inhibitors AG1478 or PP3 block FXII signaling. The MEK inhibitor PD98059 blocks FXII-induced ERK1/2 phosphorylation. LY294002, a PI3 kinase inhibitor, blocks FXII-induced Akt phosphorylation. Crosstalk between pERK1/2 and pAkt systems also occurs. Cleaved forms of HK (HKa) block binding of FXII to endothelial cells. Inhibition of any step of the FXII signaling pathways blocks cell proliferation and angiogenesis in HUVEC and aortic segments, respectively. Modified from Falati et al⁵⁶  with permission.