Caveolin-1 regulates the secretion and cytoprotection of Cyr61 in hyperoxic cell death

Cysteine-rich 61 (cyr61) belongs to the ccn family and mediates cell roliferationsurvival, and apoptosis. Ourprevious studies showed that cyr61 protected against hyperoxia-induced lung cell death via akt phosphorylation. Caveolin-1 (cav-1), a 22-kda transmembrane scaffolding protein, is the principal structural component of caveolae.Emerging data show that cav-1 regulates signal transduction-associated proteins that reside in the caveolae.Numerous integrin-related pathways, including pi3k/akt-induced cell survival are controlled by cav-1-mediatedsignaling. Our data showed that recombinant cyr61 promoted cell proliferation and resistance to hyperoxia-inducedcell death in vitro. Neutralizing antibodies reversed the above effects, indicating functional role of secreted cyr61 inresponse to hyperoxic stress. While deletion of cav-1 protected cells from hyperoxia-induced cell death,cyr61-neutralizing antibodies abolished this protective effect. Furthermore, cyr61 and cav-1 colocalized and physically interacted via integrins in bronchial epithelial cells. Deletion of cav-1 increased extracellular and decreased cytosoliccyr61, both in vitro and in vivo. Pretreatment with brefeldin a increased intracellular cyr61 in cav-1 ^-/- cells, while decreasing extracellular cyr61. Taken together, cav-1/cyr61 interaction via integrins represents a novel pathwayof cyr61 signaling involving cav-1-dependent processes, which play a critical role in regulating hyperoxia-induced celldeath.