αvβ5 integrin-dependent programmed cell death triggered by a peptide mimic of annexin V

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 beta5 integrin subunit. We show that a peptide selected for binding specifically to the beta5 cytoplasmic domain (VVI SYSMPD) 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 beta5 null cells. Finally, we show that the VVISYSMPD peptide is a mimic of annexin V. Our results suggest a functional link between the alphavbeta5 integrin, annexin V, and programmed cell death. We propose the term "endothanatos" to designate this phenomenon.