title: FERM domain promotes resveratrol-induced apoptosis in endothelial cells via inhibition of NO production.
abstract: Focal adhesion kinase (FAK) consists of an N-terminal band 4.1; ezrin, radixin, moesin (FERM) domain; tyrosine kinase domain; and C-terminal FA targeting domain. Here we show that ectopically expressed FERM is largely located in the cytosolic fraction under quiescent conditions. We further found that this ectopically expressed FERM domain aggravates endothelial cell apoptosis triggered by 100 μM resveratrol, whereas FERM had no effect on apoptosis induced by TNF-α. We determined that resveratrol at low doses (<20 μM) promotes phosphorylation (S1177) of eNOS via an AMPK-dependent pathway. The presence of the FERM domain blocked this resveratrol-stimulated eNOS phosphorylation and NO production. Thus, the pro-apoptotic activity of cytosolic FERM domain is at least partially mediated by down-regulation of NO, a critical cell survival factor. Consistently, we found that the apoptosis induced by cytosolic FERM in the presence of resveratrol was reversed by an NO donor, SNAP. In conclusion, FERM located in the cytosolic fraction plays a pivotal role in aggravating cell apoptosis through diminishing NO production.
authors.affiliation: Department of Molecular Biology & Institute of Nanosensor and Biotechnology, Dankook Univiersity, 126, Jukjeon-dong, Suji-gu, Yongin-si, Gyeonggi-do 448-701, Republic of Korea.
authors.forename: Hye-Rim
authors.initials: HR
authors.lastname: Lee
authors.forename: Jongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Jinsun
authors.initials: J
authors.lastname: Park
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Ahn
authors.forename: Eunsil
authors.initials: E
authors.lastname: Jeong
authors.forename: Heonyong
authors.initials: H
authors.lastname: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002417:Cattle; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000502:physiology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D000077185:Resveratrol; D013267:Stilbenes; D000099149:Ezrin; C071058:moesin; C071776:radixin
keywords: AMP-activated protein kinase; AMPK; Apoptosis; BAEC; CAM; ECM; Endothelial cells; FA; FAK; FAK-related non-kinase; FAT; FERM; FERM domain; FRNK; NES; NO; NTS; Resveratrol; S-Nitroso-N-acetyl-dl-penicillamine; SNAP; X-chromosome linked inhibitor of apoptosis protein; XIAP; band 4.1, ezrin, radixin, moesin domain; bovine aortic endothelial cell; cell adhesion molecule; eNOS; endothelial nitric oxide synthase; extracellular matrix; focal adhesion; focal adhesion kinase; focal adhesion targeting; nitric oxide; nuclear export signal sequence; nuclear target sequence; siRNA; small interfering RNA