The angiotensin (Ang) IV analog norleual [Nle-Tyr-Ile-psi-(CH2-NH2)(3-4)-His-Pro-Phe] exhibits structural homology with the hinge (linker) region of hepatocyte growth factor (HGF) and is hypothesized to act as a hinge region mimic. Norleual competitively inhibited the binding of HGF to its receptor c-Met in mouse liver membranes, with an IC(50) value of 3 pM. Predictably, norleual was able to inhibit HGF-dependent signaling, proliferation, migration, and invasion in multiple cell types at concentrations in the picomolar range. Ex vivo studies demonstrated that norleual exhibited potent antiangiogenic activity, an attribute that would be predicted for a HGF/c-Met antagonist. Furthermore, norleual suppressed pulmonary colonization by B16-F10 murine melanoma cells, which are characterized by an overactive HGF/c-Met system. Together, these data suggest that AngIV analogs exert at least some of their biological activity through interference with the HGF/c-Met system and may have utility as therapeutic agents in disorders that are dependent on an intact HGF/c-Met system. Finally, the ability of norleual to induce marked biological responses in human embryonic kidney cells, which do not express insulin-responsive aminopeptidase (IRAP), coupled with the observed effects of norleual on the HGF/c-Met system, casts doubt on the physiological significance of AngIV-dependent inhibition of IRAP.