TMPRSS4 is a novel type II transmembrane
serine protease that is highly expressed on the cell surface in pancreatic, thyroid and other
cancer tissues, although its oncogenic significance and molecular mechanisms are unknown. Previously, we have shown that TMPRSS4 promotes invasion, migration and
metastasis of human
tumor cells by facilitating an epithelial-mesenchymal transition (EMT). In this study, we explored the molecular basis underlying TMPRSS4-mediated effects. We show that multiple downstream signaling pathways, including
focal adhesion kinase (FAK),
extracellular signal-regulated kinase (ERK), Akt, Src and Rac1, are activated by TMPRSS4 expression and that FAK signaling and ERK activation are required for TMPRSS4-induced invasiveness and EMT, including
cadherin switch. Inhibition of PI3K or Src reduced invasiveness and actin rearrangement mediated by TMPRSS4 without restoring
E-cadherin expression. Downregulation of
E-cadherin was required for TMPRSS4-mediated effects but was not sufficient to induce EMT and invasion. TMPRSS4 induced
integrin alpha5 expression and its signal transduction, leading to invasiveness and EMT accompanied by downregulation of
E-cadherin. Functional blocking confirmed that
integrin alpha5beta1 is a critical signaling molecule that is sufficient to induce TMPRSS4-mediated effects. Immunohistochemical analysis showed that TMPRSS4 expression was significantly higher in human
colorectal cancer tissues from advanced stages than in that of early stage. Furthermore, upregulation of TMPRSS4 was correlated with enhanced
integrin alpha5 expression. These observations implicate
integrin alpha5 upregulation as a molecular mechanism by which TMPRSS4 induces invasion and contributes to
cancer progression.