Tissue factor-induced protease-activated receptor 2 signalling. (a) When the cytoplasmic domain is nonphosphorylated, tissue factor (TF) exerts a negative regulatory control on protease-activated receptor (PAR)-2 and inhibits signalling. (b) Binding of activated factor VII (FVIIa) to TF results in proteolytic cleavage of PAR-2 and phosphorylation of the cytoplasmic domain of TF via activation of phosphatidylcholine-specific phospholipase C (PC-PLC) and protein kinase C (PKC) alpha. Phosphorylation releases the negative regulatory control of PAR-2-mediated signalling, resulting in activation of several mitogen-activated protein kinase (MAPK) pathways and subsequent gene transcription. Phosphatidylinositol 3-kinase (PI3K) and Rac1 activation also constitute important signal transduction cascades, mainly related to antiapoptotic and migration processes. The constitutive association of α3β1 integrin with aggressive breast cancer cells (for example, MDA-MB-231 cells) implies that tumour cells have lost the ability to sense extracellular gradients of coagulation proteases and constitutively couple TF and integrin signalling. Although the precise mechanism for this coupling is unknown, it may play a role in tumour cell invasiveness. The overall activation of these signalling pathways is responsible for the induction of angiogenesis, malignant cell survival and metastasis, resulting in tumour growth and disease progression. BTCM, breast tumour cell membrane; Cyr61, cysteine-rich angiogenic inducer 61; CTGF, connective tissue growth factor; EC, endothelial cell; Egr-1, early growth response gene 1; ERK, extracellular signal-related kinase; JNK, c-jun N-terminal kinase; PKB, protein kinase B; TSP, thrombospondin; uPAR, urokinase-type plasminogen activator receptor; VEGF, vascular endothelial growth factor.