Adaptor Protein Cerebral Cavernous Malformation 3 (CCM3) Mediates Phosphorylation of the Cytoskeletal Proteins Ezrin/Radixin/Moesin by Mammalian Ste20-4 to Protect Cells from Oxidative Stress

• Published in: The Journal of biological chemistry Vol. 287; no. 14; pp. 11556 - 11565
• Main Authors: Fidalgo, Miguel, Guerrero, Ana, Fraile, María, Iglesias, Cristina, Pombo, Celia M., Zalvide, Juan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.03.2012; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Apoptosis Regulatory Proteins - metabolism; Cavernoma; CCM3; Cell Biology; Cell Death; Cell Line; Cytoskeletal Proteins - metabolism; Ezrin; GCKIII Kinase; Golgi; Humans; Membrane Proteins - metabolism; Microfilament Proteins - metabolism; Oxidative Stress; Phosphoproteins - metabolism; Phosphorylation; Protein Kinases; Protein Transport; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Signal Transduction; Oxidative Stress; Protein Kinases; Signal Transduction; Cell Death; Ezrin; GCKIII Kinase; Cavernoma; CCM3; Golgi
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.320259

While studying the functions of CCM3/PDCD10, a gene encoding an adaptor protein whose mutation results in vascular malformations, we have found that it is involved in a novel response to oxidative stress that results in phosphorylation and activation of the ezrin/radixin/moesin (ERM) family of proteins. This phosphorylation protects cells from accidental cell death induced by oxidative stress. We also present evidence that ERM phosphorylation is performed by the GCKIII kinase Mst4, which is activated and relocated to the cell periphery after oxidative stress. The cellular levels of Mst4 and its activation after oxidative stress depend on the presence of CCM3, as absence of the latter impairs the phosphorylation of ERM proteins and enhances death of cells exposed to reactive oxygen species. These findings shed new light on the response of cells to oxidative stress and identify an important pathophysiological situation in which ERM proteins and their phosphorylation play a significant role. Background: The adaptor protein cerebral cavernous malformation 3 (CCM3) is involved in cell death. Results: Ezrin/radixin/moesin (ERM) proteins are phosphorylated after oxidative stress, and this requires CCM3 and the ERM kinase Mst4. Conclusion: CCM3 is necessary for ERM protein phosphorylation after stress, which enhances survival. Significance: This is a novel, functionally significant pathway that protects cells from death.