Redox regulation of anoikis: reactive oxygen species as essential mediators of cell survival.
Proper attachment to the extracellular matrix (ECM) is essential for cell survival. The loss of integrin-mediated cell-ECM contact results in an apoptotic process termed anoikis. However, mechanisms involved in regulation of cell survival are poorly understood and mediators responsible for anoikis have not been well characterized. Here, we demonstrate that reactive oxygen species (ROS) produced through the involvement of the small GTPase Rac-1 upon integrin engagement exert a mandatory role in transducing a pro-survival signal that ensures that cells escape from anoikis. In particular, we show that ROS are responsible for the redox-mediated activation of Src that trans-phosphorylates epidermal growth factor receptor (EGFR) in a ligand-independent manner. The redox-dependent phosphorylation of EGFR activates both extracellular signal-regulated protein kinase and Akt downstream signalling pathways, culminating in degradation of the pro-apoptotic protein Bim. Hence, our results shed new light on the mechanism granting the adhesion-dependent antiapoptotic effect, highlighting a fundamental role of ROS-mediated Src regulation in ensuring anoikis protection.
Giannoni
E
E
Department of Biochemical Sciences, University of Florence, Florence, Italy.
Buricchi
F
F
Grimaldi
G
G
Parri
M
M
Cialdai
F
F
Taddei
M L
ML
Raugei
G
G
Ramponi
G
G
Chiarugi
P
P
D023102:Anoikis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D016023:Integrins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D066246:ErbB Receptors; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020830:rac1 GTP-Binding Protein