PKC zeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5

Title
PKC zeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5
Author(s)
파트리지아 니그로[파트리지아 니그로]주니치 아베[주니치 아베]우창훈키미오 사토[키미오 사토]캐롤린 맥클레인[캐롤린 맥클레인]마이클 오델[마이클 오델]이학주[이학주]임재향[임재향]지안동 리[지안동 리]허경선[허경선]케이기 후지와라[케이기 후지와라]브레드포드 버크[브레드포드 버크]
Keywords
NITRIC-OXIDE SYNTHASE; TUMOR-NECROSIS-FACTOR; KINASE 1 BMK1; INTERCELLULAR-ADHESION MOLECULE-1; SIGNAL-REGULATED KINASE-5; KRUPPEL-LIKE FACTOR-2; DOUBLE-KNOCKOUT MICE; APOE-DEFICIENT MICE; ENDOTHELIAL-CELLS; FACTOR-ALPHA
Issue Date
201009
Publisher
AMER SOC HEMATOLOGY
Citation
BLOOD, v.116, no.11, pp.1971 - 1979
Abstract
PKC zeta has emerged as a pathologic mediator of endothelial cell dysfunction, based on its essential role in tumor necrosis factor alpha (TNF alpha)-mediated inflammation. In contrast, extracellular signal-regulated kinase 5 (ERK5) function is required for endothelial cell homeostasis as shown by activation of Kruppel-like factor 2 (KLF2), increased endothelial nitric-oxide synthase (eNOS) expression, and inhibition of apoptosis. We hypothesized that protein kinase C zeta (PKC zeta) activation by TNF alpha would inhibit the ERK5/KLF2/eNOS pathway. TNF alpha inhibited the steady laminar flow-induced eNOS expression, and this effect was reversed by the dominant-negative form of PKC zeta (Ad.DN-PKC zeta). In addition, ERK5 function was inhibited by either TNF alpha or the transfection of the catalytic domain of PKC zeta. This inhibition was reversed by PKC zeta small interfering RNA. PKC zeta was found to bind to ERK5 under basal conditions with co-immunoprecipitation and the mammalian 2-hybrid assay. Furthermore, PKC zeta phosphorylates ERK5, and mutation analysis showed that the preferred site is S486. Most importantly, we found that the predominant effect of TNF alpha stimulation of PKC zeta was to decrease eNOS protein stability that was recapitulated by transfecting Ad. ERK5S486A mutant. Finally, aortic en face analysis of ERK5/PKC zeta activity showed high PKC zeta and ERK5 staining in the athero-prone region. Taken together our results show that PKC zeta binds and phosphorylates ERK5, thereby decreasing eNOS protein stability and contributing to early events of atherosclerosis. (Blood. 2010; 116(11): 1971-1979)
URI
http://hdl.handle.net/YU.REPOSITORY/23628http://dx.doi.org/10.1182/blood-2010-02-269134
ISSN
0006-4971
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의과대학 > 약리학교실 > Articles
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