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 proliferation, survival, and apoptosis. Our previous 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-mediated signaling. Our data showed that recombinant Cyr61 promoted cell proliferation and resistance to hyperoxia-induced cell death in vitro. Neutralizing antibodies reversed the above effects, indicating functional role of secreted Cyr61 in response 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 cytosolic Cyr61, 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 pathway of Cyr61 signaling involving cav-1-dependent processes, which play a critical role in regulating hyperoxia-induced cell death.
Jin
Yang
Y
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Kim
Hong Pyo
HP
Cao
Jiaofei
J
Zhang
Meng
M
Ifedigbo
Emeka
E
Choi
Augustine M K
AM
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D051242:Caveolin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D055515:Cysteine-Rich Protein 61 / Q000276:immunology / Q000378:metabolism*; D019610:Cytoprotection / Q000187:drug effects*; D005089:Exocytosis; D005786:Gene Expression Regulation; D039564:Integrin alphaV / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding
D000906:Antibodies; D051242:Caveolin 1; D055515:Cysteine-Rich Protein 61; D039564:Integrin alphaV
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