In vivo phage display is a powerful method to study organ-and tissue-specific vascular addresses. Using this approach, peptides capable of tissue-specific homing can be identified by performing a selection for that trait in vivo. We recently showed that the CGFECVRQCPERC (termed GFE-1) peptide can selectively bind to mouse lung vasculature after an intravenous injection. Our aim in the present study was to identify the receptor for this lung-homing peptide. By using affinity chromatography, we isolated a 55-kDa lung cell-surface protein that selectively binds to the GFE-1 peptide. Protein sequencing established the identity of the receptor as membrane dipeptidase (MDP), a cell-surface zinc metalloprotease involved in the metabolism of glutathione, leukotriene D 4 , and certain -lactam antibiotics. Phage particles displaying the GFE-1 peptide selectively bind to COS-1 cells transfected with the murine MDP cDNA. Moreover, the synthetic GFE-1 peptide could inhibit MDP activity. By establishing MDP as the receptor for the GFE-1 peptide, our results suggest potential applications for both MDP and the GFE-1 peptide in delivery of compounds to the lungs. This work also demonstrates that cell-surface proteases can be involved in tissuespecific homing.Phage display libraries are used to obtain defined peptide sequences interacting with a particular molecule (1-5). We recently used phage display libraries to select in vivo for peptides capable of homing to the vasculature of a given organ or tissue (6-8). This approach consists of intravenously injecting a phage library into a mouse, allowing the phage to circulate in vivo, and then collecting phage bound to the vascular bed of interest. By using this strategy, we identified phage-displayed peptides capable of homing to the vasculature of brain, kidney, lung, skin, pancreas, intestine, uterus, adrenal gland and prostate 1 (6, 7). We also identified peptides that selectively home to blood vessels of experimental tumors in nude mice (8). When coupled to the anti-cancer drug doxorubicin, these tumor-homing peptides enhanced the efficacy of doxorubicin against human breast cancer xenografts and reduced its overall toxicity (8).There are many reports of tissue-specific interactions between blood cells and endothelial cells. Most of the cases studied at a molecular level involve lymphocyte homing and are generally mediated by classical cell-cell adhesion molecules (9). Another example of vascular bed-specific recognition is the preference of metastasizing tumor cells for certain organs (10, 11). In the lung, several vascular receptors mediate adhesion of metastatic cells. For example, Elble et al. (12) showed that lung endothelial cell adhesion molecule-1, an endothelial surface protein with sequence homology to chloride channels, mediates adhesion of malignant melanoma cells to lung endothelium. The same group also showed that a protease, lung endothelial dipeptidyl peptidase IV, is responsible for homing of metastatic breast and prostate carcinoma cells to lung (13). These ...