The diverse cytoplasmic domain sequences within the various integrin subunits are critical for integrin-mediated signaling into the cell (outside-in signaling) and for activation of ligand binding affinity (inside-out signaling). Here we introduce an approach based on phage display technology to identify molecules that specifically interact with the cytoplasmic domain of the beta 5 integrin subunit. We show that a peptide selected for binding specifically to the beta 5 cytoplasmic domain (VVISYSMPD) induces apoptosis upon internalization. The cell death process induced by VVISYSMPD is sensitive to modulation by growth factors and by protein kinase C (PKC), and it cannot be triggered in beta 5 null cells. Finally, we show that the VVISYSMPD peptide is a mimic of annexin V. Our results suggest a functional link between the alpha v beta 5 integrin, annexin V, and programmed cell death. We propose the term "endothanatos" to designate this phenomenon.